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Bacterial pneumonia in kidney transplant recipients
Respiratory Medicine 137 (2018) 89–94
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Review article
Bacterial pneumonia in kidney transplant recipients a
b
c
D. Wilmes , E. Coche , H. Rodriguez-Villalobos , N. Kanaan
T
d,∗
a
Division of Internal Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium Division of Radiology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium Division of Microbiology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium d Division of Nephrology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Immunosuppression Organ transplantation Opportunistic Legionella Nocardia Mycobacteria Rhodococcus
Bacterial pathogens are the most frequent cause of pneumonia after transplantation. Early after transplantation, recipients are at higher risk for nosocomial infections. The most commonly encountered pathogens during this period are gram-negative bacilli (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa …), but grampositive coccus such as Staphylococcus aureus or Streptococcus pneumoniae and anaerobic bacteria can also be found. Empirical antibiotic therapy should be guided by previous colonisation of the recipient and bacterial resistance pattern in the hospital. Six months after transplantation, pneumonias are mostly due to communityacquired bacteria (S. pneumonia, H. influenza, Mycoplasma, Chlamydia and others). Opportunistic pathogens take advantage of the state of immunosuppression which is usually highest from one to six months after transplantation. During this period, but also occurring many years later in the setting of a chronically depressed immune system, bacterial pathogens with low intrinsic virulence can cause pneumonia. The diagnosis of pneumonia caused by opportunistic pathogens can be challenging. The delay in diagnosis preventing the early instauration of adequate treatment in kidney transplant recipients with a depressed immune system, frequently coupled with co-morbid conditions and a state of frailty, will affect prognosis and outcome, increasing morbidity and mortality. This review will focus on the most common opportunistic bacterial pathogens causing pneumonia in kidney transplant recipients: Legionella, Nocardia, Mycobacterium tuberculosis/nontuberculous, and Rhodococcus. Recognition of their specificities in the setting of immunosuppression will allow early diagnosis, crucial for initiation of effective therapy and successful outcome. Interactions with immunosuppressive therapy should be considered as well as reducing immunosuppression if necessary.
1. Introduction Over the past decades, the use of potent immunosuppressive therapy has improved graft survival after kidney transplantation, at the expense however, of increased susceptibility to infections [1]. Pneumonia remains one of the most common infections in kidney transplant recipients (KTR), with non-negligible morbidity and mortality [1] [2]. Bacterial pathogens are the most frequent cause of pneumonia after transplantation [3]. Early after transplantation, recipients are at higher risk for nosocomial infections. Longer duration of hospitalisation prior to surgery, multiple treatments by antibiotics and prolonged intubation increase further the risk of pneumonia caused by resistant bacteria. The most commonly encountered pathogens are gram-negative bacilli (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa …), but gram-positive coccus such as Staphylococcus aureus or Streptococcus pneumoniae and anaerobic bacteria can also be found. Empirical
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antibiotic therapy should be guided by previous colonisation of the recipient and bacterial resistance pattern in the hospital. Six months after transplantation, pneumonias are mostly due to community-acquired bacteria (S. pneumonia, H. influenza, Mycoplasma, Chlamydia and others). Opportunistic pathogens take advantage of the state of immunosuppression which is usually highest from one to six months after transplantation [1]. During this period, but also occurring many years later in the setting of a chronically depressed immune system, bacterial pathogens with low intrinsic virulence can cause pneumonia. The diagnosis of pneumonia caused by opportunistic pathogens can be challenging because symptoms can be discrete with sometimes muted clinical and radiological features due to impaired inflammatory response. The delay in diagnosis preventing the early instauration of adequate treatment in kidney transplant recipients with a depressed immune system, frequently coupled with co-morbid conditions and a state of frailty, will affect prognosis and outcome, increasing morbidity
Corresponding author. Division of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate, 10, B-1200, Brussels, Belgium. E-mail address: [email protected] (N. Kanaan).
https://doi.org/10.1016/j.rmed.2018.02.022 Received 14 November 2017; Received in revised form 6 February 2018; Accepted 26 February 2018 Available online 06 March 2018 0954-6111/ © 2018 Elsevier Ltd. All rights reserved.
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3. Nocardia species
and mortality. This review will focus on the most common opportunistic bacterial pathogens causing pneumonia in KTR, describing their clinical presentation, radiological features, laboratory and diagnostic procedures, and treatments. Recognition of these specificities in the setting of immunosuppression will allow early diagnosis, crucial for initiation of effective therapy and successful outcome.
Nocardia is a genus of the aerobic actinomycetes, partially of acidfast nature. It can cause rare opportunistic infection. In transplanted patients, the main risk factors are high-dose corticosteroids, Cytomegalovirus (CMV) disease in the preceding six months and high serum levels of CNI within the preceding thirty days [18]. In KTR, the current incidence is estimated between 0,04 and 0,7% [19]. Reviewing Nocardia infection in 66 KTR, Yu et al. found that the infection occurred 26 days to 22 years after kidney transplantation [20]. Patients with pulmonary Nocardiosis are most often infected by inhalation of contaminated particles from soil, decaying vegetation, fresh or salty water. Dissemination occurs in 30%. The most frequent secondary localisations are the skin/subcutaneous tissues and the brain, justifying cerebral magnetic resonance imaging in patients with proven pulmonary Nocardiosis. Generally, patients with pulmonary Nocardia sp involvement do not present with typical symptoms or signs of bacterial pneumonia. On chest X-Ray and lung CT, infiltrates or nodules can be found (Fig. 1). Cavitation may occur in these nodules in 1/3 of cases, and a halo sign can be observed. Diagnosis relies on the identification of the microorganism in respiratory specimens, skin biopsy (if involved) or aspirates from deep collections. Direct examination using Gram staining (Fig. 2) reveals filamentous and branching Gram-positive rods frequently surrounded with polymorphonuclear cells. Biopsy of the lesion, bronchoalveolar lavage, and tracheal or bronchial aspiration give the diagnosis in only 24%, 20% and 14% respectively [20]. The modified acid-fast stain used on sample smears may help to detect easier this organism. Microbiologists should be informed of Nocardia sp suspicion because the diagnosis can be missed by routine laboratory methods. Indeed, culture of respiratory specimens should be observed for more than 48 h, and incubated for at least 3 weeks (Table 1). Accurate identification at species level by molecular tools is particularly important, as the different species show different susceptibility patterns to antibiotics. Empiric treatment should associate two or more intravenous antibiotics effective in Nocardiosis, adapted to penetrate the central nervous system (CNS) if involved, and preferably not interacting with immunosuppressive treatment. In the case of KTR, pulmonary involvement is frequently secondary to infection by Nocardia asteroides and Nocardia farcinica. Generally high dose TMP-SMX (10–20 mg TMP and 50–100 mg SMX) is included in the initial association therapy, which should last for three to six weeks [21]. After this period, TMPSMX doses can be reduced safely. Alimentary system discomfort and rise in creatinine may develop. Duration of treatment should be 6 month minimum, and at least 12 month if CNS is affected. A prophylactic dose of TMP-SMX should be continued as secondary prophylaxis especially in patients on high maintenance immunosuppressive treatment; ideally at the dose of one double-strength tablet/day or, if tolerance is low, one single-strength tablet/day. If possible, immunosuppression should be decreased. One year after the end of the treatment, a control CT should be done.
2. Legionella species The Legionellaceae are a diverse group of aerobic fastidious Gramnegative rods. The natural reservoir is aqueous or soil environment. Transplant recipients are particularly susceptible to Legionella infection due to defective cell-mediated immunity induced by immunosuppressive medications [4]. The infection occurs most commonly in the first 3 months after transplantation, but may also occur several years later [5]. Legionnaires' disease, the pneumonic form of legionellosis, is usually acquired by inhalation or aspiration of Legionella from contaminated water environments [6]. Travel, including aboard a cruise ship or a ferry, and hotel stays are major risk factors for legionellosis [7]. Person to person transmission has not been reported. The majority of community-acquired cases are caused by strains belonging to Legionella pneumophila serogroup 1 [8]. Among this serogroup, the Pontiac subtype is predominant in isolates from community acquired infections but less common in nosocomial infection and immunocompromised patients. The initial clinical picture may be confusing because the systemic symptoms can be more impressive than those referable to the lower respiratory tract. Especially diarrhea and abdominal pain may occur as well as mental confusion. Also laboratory findings with hyponatremia and elevated transaminases can blur the diagnosis at presentation. Chest X-Ray shows alveolar filling infiltrates that vary from patchy infiltrates to multiple areas of consolidation. Chest CT findings include ground-glass opacities and consolidation. Cavitation of consolidated lung is seen in about 10% of immunosuppressed patients [9]. [10]. Currently the vast majority of Legionellosis cases are detected by urinary–antigen detection and in general the antigen assay is more sensitive than culture [11]. Because these methods are focused on the serogroup 1, and more particular on the Pontiac subtype, the urinaryantigen assay does not reliably detect other Legionella serogroups or species [12]. The test sensitivity depends on the disease's severity (severe disease is likely to be more positive). The direct fluorescent antibody test uses a monoclonal antibody (mAb) that detects all serogroups of L. pneumophila and thus has a broader spectrum [13]. It is available within 3–4 h with a sensitivity ranging from 25 to 66% [14]. Culturing Legionella strains is still the gold standard method but suffers from moderate sensitivity and requires special media and expertise [11]. PCR assays including a point-of-care technology with a syndromic approach can detect this organism directly in respiratory samples [15]. Serology testing is a valuable tool for retrospective epidemiology studies but is less useful for rapid laboratory diagnosis since the seroconversion is usually detected within 3–4 weeks, but may take up to 10 weeks [16] (Table 1). The preferred treatment for Legionnaires' disease in immunocompromised patients is azithromycin 500 mg qd for 7–10 days or levofloxacin 500 mg qd for 10–14 days. Some studies have shown better clinical response with fluoroquinolones compared with older macrolides, including faster resolution of pneumonia symptoms, a more rapid achievement of clinical stability, and shorter length of hospital stay [17]. Second choice treatments are moxifloxacin, ciprofloxacin or erythromycin associated with rifampicin. As erythromycin and rifampicin can interact with calcineurin inhibitors (CNI) trough levels (Table 2), we usually avoid these drugs, unless necessary. Sometimes, treatment duration must be prolonged depending on clinical and radiological evolution [10].
4. Mycobaterium species 4.1. Mycobacterium tuberculosis The incidence of tuberculosis (TB) among solid organ transplanted (SOT) recipients depends on the geographic area, and is estimated to be 20 to 74 times higher than in the non-transplanted population. Among KTR, the incidence varies from 0,5%–15% in endemic regions [22]. Pulmonary tuberculosis after kidney transplantation is caused mainly by reactivation of latent infection by Mycobacterium tuberculosis (LTBI). Primary infection has also been reported in the context of outbreak of tuberculosis among KTR [22] [23]. In 5% of cases, transmission is donor-derived. In kidney transplant candidates, unrecognized LTBI can lead to fatal 90
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Table 1 Opportunistic bacterial pathogens and lung involvement. Microorganism
Route of contamination
Radiological pattern
Diagnostic tests
Treatment
Distinctive features
Legionnella
inhalation/aspiration travel history (cruises/ hotel stay)
infiltrates/consolidation GGO/cavitations
Urinary antigen Molecular biology/ Culture (BAL)
Azithromycin or levofloxacin
diarrhea/abdominal pain hyponatremia/ elevated ALT-AST
Nocardia
inhalation
infiltrates with consolidation/ nodules/excavations/GGO
direct examination Culture (BAL, sputum)
TMP-SMX + Imipenem
dissemination to CNS frequent culture for > 48 hours
Mycobatrium TBC
reactivation of LTBC inhalation
infiltrates/nodules/cavitation miliary/pleural effusion
TST/IGRA Direct examination (Ziehl) Culture (BAL, sputum) Molecular biology
INH INH + RFP + PZM ± ETM
for 9 months after TP for 2 months
INH + RFP
for at least 4 months
Culture (BAL, sputum,biopsy) Molecular biology
Macrolide + RFP + ETM
culture (−) for 12 months
Culture (BAL, blood, sputum)
Quinolone + macrolide + RFP§
NonTBC Mycobacteria
inhalation
nodules/cavitation bronchiectasies with nodules
Rhodococcus Equi
Inhalation/ direct-/ indirect contact with horses
necrotic/nodules/cavitations
while under tretament for 6 months§ /culture for > 48 hours
GGO: ground-glass opacities; PCR: polymerase chain reaction; BAL: bronchoalveolar lavage; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TMP-SMX: trimethoprimsulfamethoxazole; CNS: central nervous system; TST: tuberculin skin test; IGRA: interferon-γ release assay; INH: isoniazid; RFP: rifampicin; PZM: pyrazinamide; ETM: ethambutol; BC: blood culture; §: no consensus.
Table 2 Potential interactions between CNI/mTOR inhibitors and antimicrobial agents. Anti-infective agent
Interaction with CYP3A4
Interaction with P-gp
Adjustment of CNI/ mTOR i
Azithromycin Clarithromycin Erythromycin Levofloxacin Ciprofloxacin Rifampicin Isoniazid Ethambutol TMP-SMX
no inhibition inhibition no no Induction no no no
Inhibition Inhibition inhibitor no no induction no no no
monitor Reduce dose Reduce dose no no increase dose no no no
TMP-SMX: trimethoprim-sulfamethoxazole; CYP3A4: cytochrome P450 3A4; P-gp: Pglycoprotein; CNI: calcineurin inhibitors; mTOR i: mammalian target of rapamycin inhibitor. Fig. 2. Gram stain showing filamentous and branching Gram-positive rods surrounded with polymorphonuclear cells (1000X).
disseminated disease after transplantation as a consequence of immunosuppressive therapy. Thus, prior screening is recommended. Two available tests can be used: the tuberculin skin test (TST) and/or the interferon-γ release assay (IGRA). Both tests have lower sensitivity in immunocompromised patients. IGRA testing may be preferred to TST in transplant candidates with end-stage renal disease and/or a prior history of BCG vaccination, as IGRA results will not be impacted by prior receipt of BCG. Because of the lack of sensitivity of screening tests in this population, treatment is also recommended in patients with past
history of untreated latent tuberculosis or findings suggestive of prior tuberculosis infection on chest radiography [24]. The recommended treatment for LTBI is oral isoniazid 5 mg/kg with a maximum dose of 300 mg daily, for 9 months after transplantation (Table 1). The risk of hepatotoxicity due to isoniazid in KTR without underlying liver disease is low [25]. Nevertheless, monitoring serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin at 2-week intervals Fig. 1. A 75-year-old man was admitted 17 years after kidney transplantation for altered general condition. He reported diarrhea in the last weeks and dry cough. Temperature was 37.8 °C. Chest Xray revealed a left upper lobe consolidation with no obscuration of the aortic contours. Air bronchogram was visible (A). Frontal reformatted CT confirmed the left upper lobe consolidation consistent with pneumonia. There was a slight interstitial thickening visible as septal lines at the periphery of the lesion (B). Ceftriaxone was started. One month later, Nocardia nova grew from BAL cultures. Cerebral IRM did not show any abscess. TMP-SMX was started, replaced by Ceftriaxone one month later for side effects including digestive intolerance, anemia and thrombopenia. He was treated for 6 months. Evolution was favorable.
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Fig. 3. A 54-year-old man transplanted with a kidney one year ago presented with persistent cough, fatigue, night sweats and anorexia. He had a past history of chronic obstructive pulmonary disease related to smoking. Chest radiography revealed a hazy infiltrate at the right lung apex (A). Frontal reformatted CT showed an excavated irregular pulmonary opacity at the apex of the right upper lobe (B). Several sputa revealed fluorescent auramine-positive acid-fast bacilli. Antituberculous quadritherapy including isoniazid, rifampicin, pyrazinamide and ethambutol was started. Fifteen days later, sputum cultures grew MAC, further identified as Mycobacterium intracellulare. Isoniazid and pyrazinamide were replaced by clarithromycin. Sputum cultures turned negative 3 months after treatment initiation. Antibiotics were continued for 12 months of culturenegative sputum status. Evolution was favorable.
tuberculosis, but should not be used as first-line treatment, as selective pressure may result in the emergence of quinolone-resistant Mycobacterium tuberculosis. The treatment is complicated by drug-drug interactions between anti-TB agents and immunosuppressant drugs [29]. The rifamycins (especially rifampin) are inductors of the cytochrome p450 isoenzyme CYP3A4 that lead to reduced serum concentrations of CNI and mTOR inhibitors. The doses of these immunosuppressants should be increased 3–5 fold and serum levels should be closely monitored to avoid rejection (Table 2). Another issue is the toxicity of antiTB agents. Pyridoxine should be added to prevent neurotoxicity of isoniazid and ophthalmologic follow-up offered to detect early ophthalmologic toxicity of ethambutol. The related mortality in SOT patients has improved substantially in recent years, declining from 21% to 10% [27,37].
for 6 weeks and then monthly is recommended. About 34–61% of the active tuberculosis cases occur during the first year after SOT [26] [27]. In KTR it occurs with a median time of 11.5 month after transplantation [28]. The diagnosis is often delayed because of paucisymptomatic or extrapulmonary disease. Also, the association with other infections in up to 23% of cases make the diagnosis challenging [29]. Risk factors are reported such as pretransplant clinical condition (prolonged dialysis, diabetes, cirrhosis, and hepatitis C virus infection) and the intensity of immunosuppression [27]. The most common clinical manifestation is moderate, permanent fever, more often seen in disseminated disease [28], and impairment of the general state with night sweats and weight loss. Pulmonary symptoms are observed in 37–51%, particularly coughing sometimes accompanied by spittle that can be hemorrhagic. Disseminated (18–62%) and extrapulmonary presentations (18–50%) are more frequent in transplant recipients [30–32]. Chest X-ray shows focal (40%) or diffuse interstitial infiltrate, nodules (5%), cavitary lesions (4%), miliary pattern (22%) or pleural effusion (13%) [28]. C-reactive protein is inconstantly elevated (75%) and usually at low levels as seen in CMV infection [32]. The diagnosis of active tuberculosis often requires an invasive procedure such as fiberoptic bronchoscopy with bronchoalveolar lavage, mediastinoscopy or transthoracic fine needle aspiration for biopsies. Staining and culture for acid-fast bacilli should be done on sputum and bronchoscopy specimens. Blood cultures should also be performed in patients with high fever, as the yield can be significant [33]. A positive Ziehl-Neelsen smear can raise suspicion of tuberculosis but cannot differentiate nontuberculous Mycobacteria from Mycobacterium tuberculosis. The definitive diagnosis involves the culture of Mycobacterium tuberculosis from clinical samples, but this may take up to 6 weeks. A positive polymerase chain reaction (PCR) test for Mycobacterium tuberculosis could be an alternative to culture for a more rapid confirmation of tuberculosis (Table 1). This kind of test has specificity close to 100% but has variable sensitivities, especially in the case of smear-negative disease. Another application of molecular biology techniques is the detection of mutations in Mycobacterium tuberculosis strains reported to account for a majority of M. tuberculosis clinical isolates resistant to rifampicin (RIF), a marker of multidrug-resistant tuberculosis (MDR-TB) [34]. The empirical treatment of TB in KTR associates in the first 2 months rifampicin, isoniazid, pyrazinamide and, if resistance is possible, ethambutol. The consolidation phase extends the treatment with isoniazid and rifampicin for a minimum of 4 months. Due to the frequent recurrence of TB in these patients, several authors recommend a prolonged anti-TB treatment for at least 9 months [35]. A longer duration of therapy should be considered if the infection is localized in bones or CNS, in individuals with slow culture conversion in sputum and is mandatory in some patients who are treated by second line drugs [36]. Quinolones have been studied as an alternative treatment for
4.2. Nontuberculous mycobacteria (NTM) NTM are ubiquitous organisms found in soil and water that can cause opportunistic infection in immunocompromised patients. Among SOT patients, lung transplant recipients are at higher risk of pleuropulmonary disease as a consequence of potent immunosuppression combined to underlying structural disease promoting airway colonisation [38]. [39] [40] In KTR, NTM can cause pneumonia though less frequently than cutaneous or disseminated presentation [41]. The diagnosis of pulmonary disease with NTM requires clinical, radiological and bacteriological criteria according to the American Thoracic Society [42]. Fever with persistent respiratory complaints will prompt a radiographic evaluation that can show nodular or cavitary opacities on chest X-ray or multifocal bronchiectasis with small nodules on CT scan (Fig. 3). Microbiology criteria include positive culture from respiratory specimens (2 consecutive sputa or one bronchoalveolar lavage) or from pulmonary tissue [42]. NTM grow slowly in culture, often delaying the diagnosis. Few cases of NTM pulmonary infection in KTR have been reported so far. Reviewing 14 published cases, Ho et al. identified 3 mycobacterial species mainly responsible for NTM pulmonary infections in KTR: Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium avium complex (MAC). The mean time from transplantation to onset of pulmonary disease was 33.4 months (2–120 months). Outcome was favorable in all patients but one [43].Risk factors for developing NTM pneumonia after renal transplant are not known. An underlying pulmonary disease could predispose to NTM colonisation or infection in patients under immunosuppression. NTM should be identified to the species level. Commercial DNA probes and high-performance liquid chromatography allow rapid species identification. Other techniques including extended antibiotic in vitro susceptibility testing, DNA sequencing or PCR restriction endonuclease assay may be necessary. ATS guidelines recommend a threedrug therapy in severe lung disease. The choice of antibiotics depends 92
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Conflicts of interest
on NTM species. For MAC pulmonary disease, the combination includes a macrolide (clarithromycin or azithromycin), rifampicin, and ethambutol. In a limited number of species only, the correlation between in vitro susceptibility testing and clinical outcome has been demonstrated. AFB smears and cultures of sputum must be collected monthly during therapy to assess response. A culture-negative status for 12 months while receiving the macrolide-containing regimen is required [42]. Reduction of immunosuppression must be considered. When treated adequately, the outcome of NTM lung disease is good [43].
None. Funding None. References [1] J.A. Fishman, Introduction: infection in solid organ transplant recipients, Am. J. Transplant. 9 (Suppl 4) (2009) S3–S6. [2] G. Pourmand, S. Salem, A. Mehrsai, M. Taherimahmoudi, R. Ebrahimi, M.R. Pourmand, Infectious complications after kidney transplantation: a singlecenter experience, Transpl. Infect. Dis. 9 (2007) 302–309. [3] I. Hoyo, L. Linares, C. Cervera, et al., Epidemiology of pneumonia in kidney transplantation, Transplant. Proc. 42 (2010) 2938–2940. [4] N.M. Ampel, E.J. Wing, Legionella infection in transplant patients, Semin. Respir. Infect. 5 (1990) 30–37. [5] D.B. Jernigan, L.I. Sanders, K.B. Waites, E.S. Brookings, R.F. Benson, P.G. Pappas, Pulmonary infection due to Legionella cincinnatiensis in renal transplant recipients: two cases and implications for laboratory diagnosis, Clin. Infect. Dis. 18 (1994) 385–389. [6] P.C. Luck, T. Schneider, J. Wagner, et al., Community-acquired Legionnaires' disease caused by Legionella pneumophila serogroup 10 linked to the private home, J. Med. Microbiol. 57 (2008) 240–243. [7] C. Guyard, D.E. Low, Legionella infections and travel associated legionellosis, Trav. Med. Infect. Dis. 9 (2011) 176–186. [8] J.H. Helbig, S. Bernander, P.M. Castellani, et al., Pan-European study on cultureproven Legionnaires' disease: distribution of Legionella pneumophila serogroups and monoclonal subgroups, Eur. J. Clin. Microbiol. Infect. Dis. 21 (2002) 710–716. [9] H. Yu, F. Higa, K. Hibiya, et al., Computed tomographic features of 23 sporadic cases with Legionella pneumophila pneumonia, Eur. J. Radiol. 74 (2010) e73–78. [10] G.L. Mandell, J.E. Bennett, R. Dolin, Principles and Practice of Infectious Diseases, seventh ed., Churchill Livingstone, New York, NY, USA, 2010. [11] J.W. Den Boer, E.P. Yzerman, Diagnosis of Legionella infection in Legionnaires' disease, Eur. J. Clin. Microbiol. Infect. 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Kwak, et al., Opportunistic infections in 547 organ transplant recipients receiving alemtuzumab, a humanized monoclonal CD-52 antibody, Clin. Infect. Dis. 44 (2007) 204–212. [19] D. Lebeaux, E. Morelon, F. Suarez, et al., Nocardiosis in transplant recipients, Eur. J. Clin. Microbiol. Infect. Dis. 33 (2014) 689–702. [20] X. Yu, F. Han, J. Wu, et al., Nocardia infection in kidney transplant recipients: case report and analysis of 66 published cases, Transpl. Infect. Dis. 13 (2011) 385–391. [21] R. Schlaberg, M.A. Fisher, K.E. Hanson, Susceptibility profiles of Nocardia isolates based on current taxonomy, Antimicrob. Agents Chemother. 58 (2014) 795–800. [22] P. Munoz, C. Rodriguez, E. Bouza, Mycobacterium tuberculosis infection in recipients of solid organ transplants, Clin. Infect. Dis. 40 (2005) 581–587. [23] J.A. Jereb, D.R. Burwen, S.W. Dooley, et al., Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates, J. Infect. Dis. 168 (1993) 1219–1224. [24] D.J. Horne, M. Narita, C.L. Spitters, et al., Challenging issues in tuberculosis in solid organ transplantation, Clin. Infect. Dis. 57 (2013) 1473–1482. [25] S.J. Antony, C. Ynares, J.S. Dummer, Isoniazid hepatotoxicity in renal transplant recipients, Clin. Transplant. 11 (1997) 34–37. [26] J. Liu, J. Yan, Q. Wan, Q. Ye, Y. Huang, The risk factors for tuberculosis in liver or kidney transplant recipients, BMC Infect. Dis. 14 (2014) 387. [27] J. Torre-Cisneros, A. Doblas, J.M. Aguado, et al., Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort, Clin. Infect. Dis. 48 (2009) 1657–1665. [28] N. Singh, D.L. 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5. Rhodococcus equi Among SOT recipients, KTR are at highest risk for Rhodococcus equi infection. This zoonotic organism belongs to the aerobic Actinomycetes. It is a Gram-positive, aerobic bacterium that can exist as a coccus or a bacillus and is sometimes acid-fast. It is a facultative intracellular pathogen. Half of the infected patients report a history of exposure to farm soil or to animals. Inhalation of infected aerosols and dust particles seems to be the predominant route of disease transmission, but also inoculation into a wound or mucous membrane, or ingestion and passage through the alimentary tract has been suspected. Nosocomial cases of infection, as well as patient-to-patient transmission were also suspected [44]. In a review of 2012, infection with Rhodococcus occurred mostly in immunosuppressed transplant recipients receiving a triple therapy including steroids, azathioprine or mycophenolate and a CNI. The delay between transplantation and Rhodococcus pneumonia was 3 years (3 months-19 years) [45]. Generally the disease tends to follow a subacute course with progressive cough, pleuritic chest pain, and fever often accompanied by cachexia, weight loss and fatigue. Chest X-Ray and lung CT show necrotic pneumonia, nodules or cavitary lesions, enlargement of mediastinal lymph nodes and pleural effusion. The most common radiographic image is cavitary upper-lobe pneumonia [46]. Recurrent pneumothorax and invasion of contiguous chest structures were also described. In 82% of cases the lung is the sole site of infection. In 18% of the patients, extrapulmonary infections occur, predominantly subcutaneous abscesses, bone infection and CNS involvement. The bacteria can be isolated from blood cultures (25% of transplant recipients have a concomitant bacteremia). Culture of sputum is positive in only 20% and should be held for more than 48 h [45]. Often the diagnosis needs bronchoalveolar lavage or biopsy. The biopsy usually shows pulmonary malakoplakia characterised by a dense infiltration of foamy histiocytes with intracellular coccobacilli and Michaelis-Gutmann bodies [46]. Identification of this organism is difficult. The MALDI-TOF mass spectrometry can be use, but in several cases, identification required 16S rRNA gene-sequencing [47]. Treatment associates two or three antibiotics that should be chosen according to in vitro susceptibility testing and infection foci. No standardized treatment regimen exists. Intravenous treatment for a minimum of six weeks has been proposed, until clinical and radiological improvement, and continued orally for at least six months depending on infection size and site. The preferred oral regimen includes quinolones, tetracycline (minocycline being more frequently used among KTR), and rifampicin [44] [48]. Development of resistance during treatment has been reported [45]. Recurrence is a common problem in R. equi infection with acquired resistance [49]. If possible, the treatment should be completed by surgical resection and reduction of immunosuppressive treatment. 6. Conclusion Pneumonia caused by opportunistic bacterial pathogens can be lifethreatening in KTR. Prompt recognition of the involved microorganism is crucial for initiating antibiotherapy and determining treatment duration. Interactions with immunosuppressive therapy should be considered as well as reducing immunosuppression if necessary. 93
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[31] J. Liu, J. Yan, Q. Wan, Q. Ye, Y. Huang, The risk factors for tuberculosis in liver or kidney transplant recipients, BMC Infect. Dis. 14 (2014) 387. [32] K. Boubaker, T. Gargah, E. Abderrahim, T.B. Abdallah, A. Kheder, Mycobacterium tuberculosis infection following kidney transplantation, BioMed Res. Int. 2013 (2013) 347103. [33] S.H. Schaff, A.I. Zumla, J. Grange, et al., Tuberculosis: a Comprehensive Clinical Reference, WB Saunders Elsevier, London, UK, 2009. [34] I. Mokrousov, T. Otten, B. Vyshnevskiy, O. Narvskaya, Allele-specific rpoB PCR assays for detection of rifampin-resistant Mycobacterium tuberculosis in sputum smears, Antimicrob. Agents Chemother. 47 (2003) 2231–2235. [35] H.Y. Sun, Treating tuberculosis in solid organ transplant recipients, Curr. Opin. Infect. Dis. 27 (2014) 501–505. [36] A.K. Subramanian, M.I. Morris, Mycobacterium tuberculosis infections in solid organ transplantation, Am. J. Transplant. 13 (Suppl 4) (2013) 68–76. [37] H.Y. Sun, P. Munoz, J. Torre-Cisneros, et al., Tuberculosis in solid-organ transplant recipients: disease characteristics and outcomes in the current era, Prog. Transplant. 24 (2014) 37–43. [38] B.M. Knoll, S. Kappagoda, R.R. Gill, et al., Non-tuberculous mycobacterial infection among lung transplant recipients: a 15-year cohort study, Transpl. Infect. Dis. 14 (2012) 452–460. [39] S.A. Longworth, C. Vinnard, I. Lee, K.D. Sims, T.D. Barton, E.A. Blumberg, Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case-control study, Transpl. Infect. Dis. 16 (2014) 76–83. [40] I.A. George, C.Q. Santos, M.A. Olsen, T.C. Bailey, Epidemiology and outcomes of nontuberculous mycobacterial infections in solid organ transplant recipients at a Midwestern center, Transplantation 100 (2016) 1073–1078. [41] K. Doucette, J.A. Fishman, Nontuberculous mycobacterial infection in
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Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Review article
Bacterial pneumonia in kidney transplant recipients a
b
c
D. Wilmes , E. Coche , H. Rodriguez-Villalobos , N. Kanaan
T
d,∗
a
Division of Internal Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium Division of Radiology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium Division of Microbiology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium d Division of Nephrology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Immunosuppression Organ transplantation Opportunistic Legionella Nocardia Mycobacteria Rhodococcus
Bacterial pathogens are the most frequent cause of pneumonia after transplantation. Early after transplantation, recipients are at higher risk for nosocomial infections. The most commonly encountered pathogens during this period are gram-negative bacilli (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa …), but grampositive coccus such as Staphylococcus aureus or Streptococcus pneumoniae and anaerobic bacteria can also be found. Empirical antibiotic therapy should be guided by previous colonisation of the recipient and bacterial resistance pattern in the hospital. Six months after transplantation, pneumonias are mostly due to communityacquired bacteria (S. pneumonia, H. influenza, Mycoplasma, Chlamydia and others). Opportunistic pathogens take advantage of the state of immunosuppression which is usually highest from one to six months after transplantation. During this period, but also occurring many years later in the setting of a chronically depressed immune system, bacterial pathogens with low intrinsic virulence can cause pneumonia. The diagnosis of pneumonia caused by opportunistic pathogens can be challenging. The delay in diagnosis preventing the early instauration of adequate treatment in kidney transplant recipients with a depressed immune system, frequently coupled with co-morbid conditions and a state of frailty, will affect prognosis and outcome, increasing morbidity and mortality. This review will focus on the most common opportunistic bacterial pathogens causing pneumonia in kidney transplant recipients: Legionella, Nocardia, Mycobacterium tuberculosis/nontuberculous, and Rhodococcus. Recognition of their specificities in the setting of immunosuppression will allow early diagnosis, crucial for initiation of effective therapy and successful outcome. Interactions with immunosuppressive therapy should be considered as well as reducing immunosuppression if necessary.
1. Introduction Over the past decades, the use of potent immunosuppressive therapy has improved graft survival after kidney transplantation, at the expense however, of increased susceptibility to infections [1]. Pneumonia remains one of the most common infections in kidney transplant recipients (KTR), with non-negligible morbidity and mortality [1] [2]. Bacterial pathogens are the most frequent cause of pneumonia after transplantation [3]. Early after transplantation, recipients are at higher risk for nosocomial infections. Longer duration of hospitalisation prior to surgery, multiple treatments by antibiotics and prolonged intubation increase further the risk of pneumonia caused by resistant bacteria. The most commonly encountered pathogens are gram-negative bacilli (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa …), but gram-positive coccus such as Staphylococcus aureus or Streptococcus pneumoniae and anaerobic bacteria can also be found. Empirical
∗
antibiotic therapy should be guided by previous colonisation of the recipient and bacterial resistance pattern in the hospital. Six months after transplantation, pneumonias are mostly due to community-acquired bacteria (S. pneumonia, H. influenza, Mycoplasma, Chlamydia and others). Opportunistic pathogens take advantage of the state of immunosuppression which is usually highest from one to six months after transplantation [1]. During this period, but also occurring many years later in the setting of a chronically depressed immune system, bacterial pathogens with low intrinsic virulence can cause pneumonia. The diagnosis of pneumonia caused by opportunistic pathogens can be challenging because symptoms can be discrete with sometimes muted clinical and radiological features due to impaired inflammatory response. The delay in diagnosis preventing the early instauration of adequate treatment in kidney transplant recipients with a depressed immune system, frequently coupled with co-morbid conditions and a state of frailty, will affect prognosis and outcome, increasing morbidity
Corresponding author. Division of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate, 10, B-1200, Brussels, Belgium. E-mail address: [email protected] (N. Kanaan).
https://doi.org/10.1016/j.rmed.2018.02.022 Received 14 November 2017; Received in revised form 6 February 2018; Accepted 26 February 2018 Available online 06 March 2018 0954-6111/ © 2018 Elsevier Ltd. All rights reserved.
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3. Nocardia species
and mortality. This review will focus on the most common opportunistic bacterial pathogens causing pneumonia in KTR, describing their clinical presentation, radiological features, laboratory and diagnostic procedures, and treatments. Recognition of these specificities in the setting of immunosuppression will allow early diagnosis, crucial for initiation of effective therapy and successful outcome.
Nocardia is a genus of the aerobic actinomycetes, partially of acidfast nature. It can cause rare opportunistic infection. In transplanted patients, the main risk factors are high-dose corticosteroids, Cytomegalovirus (CMV) disease in the preceding six months and high serum levels of CNI within the preceding thirty days [18]. In KTR, the current incidence is estimated between 0,04 and 0,7% [19]. Reviewing Nocardia infection in 66 KTR, Yu et al. found that the infection occurred 26 days to 22 years after kidney transplantation [20]. Patients with pulmonary Nocardiosis are most often infected by inhalation of contaminated particles from soil, decaying vegetation, fresh or salty water. Dissemination occurs in 30%. The most frequent secondary localisations are the skin/subcutaneous tissues and the brain, justifying cerebral magnetic resonance imaging in patients with proven pulmonary Nocardiosis. Generally, patients with pulmonary Nocardia sp involvement do not present with typical symptoms or signs of bacterial pneumonia. On chest X-Ray and lung CT, infiltrates or nodules can be found (Fig. 1). Cavitation may occur in these nodules in 1/3 of cases, and a halo sign can be observed. Diagnosis relies on the identification of the microorganism in respiratory specimens, skin biopsy (if involved) or aspirates from deep collections. Direct examination using Gram staining (Fig. 2) reveals filamentous and branching Gram-positive rods frequently surrounded with polymorphonuclear cells. Biopsy of the lesion, bronchoalveolar lavage, and tracheal or bronchial aspiration give the diagnosis in only 24%, 20% and 14% respectively [20]. The modified acid-fast stain used on sample smears may help to detect easier this organism. Microbiologists should be informed of Nocardia sp suspicion because the diagnosis can be missed by routine laboratory methods. Indeed, culture of respiratory specimens should be observed for more than 48 h, and incubated for at least 3 weeks (Table 1). Accurate identification at species level by molecular tools is particularly important, as the different species show different susceptibility patterns to antibiotics. Empiric treatment should associate two or more intravenous antibiotics effective in Nocardiosis, adapted to penetrate the central nervous system (CNS) if involved, and preferably not interacting with immunosuppressive treatment. In the case of KTR, pulmonary involvement is frequently secondary to infection by Nocardia asteroides and Nocardia farcinica. Generally high dose TMP-SMX (10–20 mg TMP and 50–100 mg SMX) is included in the initial association therapy, which should last for three to six weeks [21]. After this period, TMPSMX doses can be reduced safely. Alimentary system discomfort and rise in creatinine may develop. Duration of treatment should be 6 month minimum, and at least 12 month if CNS is affected. A prophylactic dose of TMP-SMX should be continued as secondary prophylaxis especially in patients on high maintenance immunosuppressive treatment; ideally at the dose of one double-strength tablet/day or, if tolerance is low, one single-strength tablet/day. If possible, immunosuppression should be decreased. One year after the end of the treatment, a control CT should be done.
2. Legionella species The Legionellaceae are a diverse group of aerobic fastidious Gramnegative rods. The natural reservoir is aqueous or soil environment. Transplant recipients are particularly susceptible to Legionella infection due to defective cell-mediated immunity induced by immunosuppressive medications [4]. The infection occurs most commonly in the first 3 months after transplantation, but may also occur several years later [5]. Legionnaires' disease, the pneumonic form of legionellosis, is usually acquired by inhalation or aspiration of Legionella from contaminated water environments [6]. Travel, including aboard a cruise ship or a ferry, and hotel stays are major risk factors for legionellosis [7]. Person to person transmission has not been reported. The majority of community-acquired cases are caused by strains belonging to Legionella pneumophila serogroup 1 [8]. Among this serogroup, the Pontiac subtype is predominant in isolates from community acquired infections but less common in nosocomial infection and immunocompromised patients. The initial clinical picture may be confusing because the systemic symptoms can be more impressive than those referable to the lower respiratory tract. Especially diarrhea and abdominal pain may occur as well as mental confusion. Also laboratory findings with hyponatremia and elevated transaminases can blur the diagnosis at presentation. Chest X-Ray shows alveolar filling infiltrates that vary from patchy infiltrates to multiple areas of consolidation. Chest CT findings include ground-glass opacities and consolidation. Cavitation of consolidated lung is seen in about 10% of immunosuppressed patients [9]. [10]. Currently the vast majority of Legionellosis cases are detected by urinary–antigen detection and in general the antigen assay is more sensitive than culture [11]. Because these methods are focused on the serogroup 1, and more particular on the Pontiac subtype, the urinaryantigen assay does not reliably detect other Legionella serogroups or species [12]. The test sensitivity depends on the disease's severity (severe disease is likely to be more positive). The direct fluorescent antibody test uses a monoclonal antibody (mAb) that detects all serogroups of L. pneumophila and thus has a broader spectrum [13]. It is available within 3–4 h with a sensitivity ranging from 25 to 66% [14]. Culturing Legionella strains is still the gold standard method but suffers from moderate sensitivity and requires special media and expertise [11]. PCR assays including a point-of-care technology with a syndromic approach can detect this organism directly in respiratory samples [15]. Serology testing is a valuable tool for retrospective epidemiology studies but is less useful for rapid laboratory diagnosis since the seroconversion is usually detected within 3–4 weeks, but may take up to 10 weeks [16] (Table 1). The preferred treatment for Legionnaires' disease in immunocompromised patients is azithromycin 500 mg qd for 7–10 days or levofloxacin 500 mg qd for 10–14 days. Some studies have shown better clinical response with fluoroquinolones compared with older macrolides, including faster resolution of pneumonia symptoms, a more rapid achievement of clinical stability, and shorter length of hospital stay [17]. Second choice treatments are moxifloxacin, ciprofloxacin or erythromycin associated with rifampicin. As erythromycin and rifampicin can interact with calcineurin inhibitors (CNI) trough levels (Table 2), we usually avoid these drugs, unless necessary. Sometimes, treatment duration must be prolonged depending on clinical and radiological evolution [10].
4. Mycobaterium species 4.1. Mycobacterium tuberculosis The incidence of tuberculosis (TB) among solid organ transplanted (SOT) recipients depends on the geographic area, and is estimated to be 20 to 74 times higher than in the non-transplanted population. Among KTR, the incidence varies from 0,5%–15% in endemic regions [22]. Pulmonary tuberculosis after kidney transplantation is caused mainly by reactivation of latent infection by Mycobacterium tuberculosis (LTBI). Primary infection has also been reported in the context of outbreak of tuberculosis among KTR [22] [23]. In 5% of cases, transmission is donor-derived. In kidney transplant candidates, unrecognized LTBI can lead to fatal 90
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Table 1 Opportunistic bacterial pathogens and lung involvement. Microorganism
Route of contamination
Radiological pattern
Diagnostic tests
Treatment
Distinctive features
Legionnella
inhalation/aspiration travel history (cruises/ hotel stay)
infiltrates/consolidation GGO/cavitations
Urinary antigen Molecular biology/ Culture (BAL)
Azithromycin or levofloxacin
diarrhea/abdominal pain hyponatremia/ elevated ALT-AST
Nocardia
inhalation
infiltrates with consolidation/ nodules/excavations/GGO
direct examination Culture (BAL, sputum)
TMP-SMX + Imipenem
dissemination to CNS frequent culture for > 48 hours
Mycobatrium TBC
reactivation of LTBC inhalation
infiltrates/nodules/cavitation miliary/pleural effusion
TST/IGRA Direct examination (Ziehl) Culture (BAL, sputum) Molecular biology
INH INH + RFP + PZM ± ETM
for 9 months after TP for 2 months
INH + RFP
for at least 4 months
Culture (BAL, sputum,biopsy) Molecular biology
Macrolide + RFP + ETM
culture (−) for 12 months
Culture (BAL, blood, sputum)
Quinolone + macrolide + RFP§
NonTBC Mycobacteria
inhalation
nodules/cavitation bronchiectasies with nodules
Rhodococcus Equi
Inhalation/ direct-/ indirect contact with horses
necrotic/nodules/cavitations
while under tretament for 6 months§ /culture for > 48 hours
GGO: ground-glass opacities; PCR: polymerase chain reaction; BAL: bronchoalveolar lavage; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TMP-SMX: trimethoprimsulfamethoxazole; CNS: central nervous system; TST: tuberculin skin test; IGRA: interferon-γ release assay; INH: isoniazid; RFP: rifampicin; PZM: pyrazinamide; ETM: ethambutol; BC: blood culture; §: no consensus.
Table 2 Potential interactions between CNI/mTOR inhibitors and antimicrobial agents. Anti-infective agent
Interaction with CYP3A4
Interaction with P-gp
Adjustment of CNI/ mTOR i
Azithromycin Clarithromycin Erythromycin Levofloxacin Ciprofloxacin Rifampicin Isoniazid Ethambutol TMP-SMX
no inhibition inhibition no no Induction no no no
Inhibition Inhibition inhibitor no no induction no no no
monitor Reduce dose Reduce dose no no increase dose no no no
TMP-SMX: trimethoprim-sulfamethoxazole; CYP3A4: cytochrome P450 3A4; P-gp: Pglycoprotein; CNI: calcineurin inhibitors; mTOR i: mammalian target of rapamycin inhibitor. Fig. 2. Gram stain showing filamentous and branching Gram-positive rods surrounded with polymorphonuclear cells (1000X).
disseminated disease after transplantation as a consequence of immunosuppressive therapy. Thus, prior screening is recommended. Two available tests can be used: the tuberculin skin test (TST) and/or the interferon-γ release assay (IGRA). Both tests have lower sensitivity in immunocompromised patients. IGRA testing may be preferred to TST in transplant candidates with end-stage renal disease and/or a prior history of BCG vaccination, as IGRA results will not be impacted by prior receipt of BCG. Because of the lack of sensitivity of screening tests in this population, treatment is also recommended in patients with past
history of untreated latent tuberculosis or findings suggestive of prior tuberculosis infection on chest radiography [24]. The recommended treatment for LTBI is oral isoniazid 5 mg/kg with a maximum dose of 300 mg daily, for 9 months after transplantation (Table 1). The risk of hepatotoxicity due to isoniazid in KTR without underlying liver disease is low [25]. Nevertheless, monitoring serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin at 2-week intervals Fig. 1. A 75-year-old man was admitted 17 years after kidney transplantation for altered general condition. He reported diarrhea in the last weeks and dry cough. Temperature was 37.8 °C. Chest Xray revealed a left upper lobe consolidation with no obscuration of the aortic contours. Air bronchogram was visible (A). Frontal reformatted CT confirmed the left upper lobe consolidation consistent with pneumonia. There was a slight interstitial thickening visible as septal lines at the periphery of the lesion (B). Ceftriaxone was started. One month later, Nocardia nova grew from BAL cultures. Cerebral IRM did not show any abscess. TMP-SMX was started, replaced by Ceftriaxone one month later for side effects including digestive intolerance, anemia and thrombopenia. He was treated for 6 months. Evolution was favorable.
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Fig. 3. A 54-year-old man transplanted with a kidney one year ago presented with persistent cough, fatigue, night sweats and anorexia. He had a past history of chronic obstructive pulmonary disease related to smoking. Chest radiography revealed a hazy infiltrate at the right lung apex (A). Frontal reformatted CT showed an excavated irregular pulmonary opacity at the apex of the right upper lobe (B). Several sputa revealed fluorescent auramine-positive acid-fast bacilli. Antituberculous quadritherapy including isoniazid, rifampicin, pyrazinamide and ethambutol was started. Fifteen days later, sputum cultures grew MAC, further identified as Mycobacterium intracellulare. Isoniazid and pyrazinamide were replaced by clarithromycin. Sputum cultures turned negative 3 months after treatment initiation. Antibiotics were continued for 12 months of culturenegative sputum status. Evolution was favorable.
tuberculosis, but should not be used as first-line treatment, as selective pressure may result in the emergence of quinolone-resistant Mycobacterium tuberculosis. The treatment is complicated by drug-drug interactions between anti-TB agents and immunosuppressant drugs [29]. The rifamycins (especially rifampin) are inductors of the cytochrome p450 isoenzyme CYP3A4 that lead to reduced serum concentrations of CNI and mTOR inhibitors. The doses of these immunosuppressants should be increased 3–5 fold and serum levels should be closely monitored to avoid rejection (Table 2). Another issue is the toxicity of antiTB agents. Pyridoxine should be added to prevent neurotoxicity of isoniazid and ophthalmologic follow-up offered to detect early ophthalmologic toxicity of ethambutol. The related mortality in SOT patients has improved substantially in recent years, declining from 21% to 10% [27,37].
for 6 weeks and then monthly is recommended. About 34–61% of the active tuberculosis cases occur during the first year after SOT [26] [27]. In KTR it occurs with a median time of 11.5 month after transplantation [28]. The diagnosis is often delayed because of paucisymptomatic or extrapulmonary disease. Also, the association with other infections in up to 23% of cases make the diagnosis challenging [29]. Risk factors are reported such as pretransplant clinical condition (prolonged dialysis, diabetes, cirrhosis, and hepatitis C virus infection) and the intensity of immunosuppression [27]. The most common clinical manifestation is moderate, permanent fever, more often seen in disseminated disease [28], and impairment of the general state with night sweats and weight loss. Pulmonary symptoms are observed in 37–51%, particularly coughing sometimes accompanied by spittle that can be hemorrhagic. Disseminated (18–62%) and extrapulmonary presentations (18–50%) are more frequent in transplant recipients [30–32]. Chest X-ray shows focal (40%) or diffuse interstitial infiltrate, nodules (5%), cavitary lesions (4%), miliary pattern (22%) or pleural effusion (13%) [28]. C-reactive protein is inconstantly elevated (75%) and usually at low levels as seen in CMV infection [32]. The diagnosis of active tuberculosis often requires an invasive procedure such as fiberoptic bronchoscopy with bronchoalveolar lavage, mediastinoscopy or transthoracic fine needle aspiration for biopsies. Staining and culture for acid-fast bacilli should be done on sputum and bronchoscopy specimens. Blood cultures should also be performed in patients with high fever, as the yield can be significant [33]. A positive Ziehl-Neelsen smear can raise suspicion of tuberculosis but cannot differentiate nontuberculous Mycobacteria from Mycobacterium tuberculosis. The definitive diagnosis involves the culture of Mycobacterium tuberculosis from clinical samples, but this may take up to 6 weeks. A positive polymerase chain reaction (PCR) test for Mycobacterium tuberculosis could be an alternative to culture for a more rapid confirmation of tuberculosis (Table 1). This kind of test has specificity close to 100% but has variable sensitivities, especially in the case of smear-negative disease. Another application of molecular biology techniques is the detection of mutations in Mycobacterium tuberculosis strains reported to account for a majority of M. tuberculosis clinical isolates resistant to rifampicin (RIF), a marker of multidrug-resistant tuberculosis (MDR-TB) [34]. The empirical treatment of TB in KTR associates in the first 2 months rifampicin, isoniazid, pyrazinamide and, if resistance is possible, ethambutol. The consolidation phase extends the treatment with isoniazid and rifampicin for a minimum of 4 months. Due to the frequent recurrence of TB in these patients, several authors recommend a prolonged anti-TB treatment for at least 9 months [35]. A longer duration of therapy should be considered if the infection is localized in bones or CNS, in individuals with slow culture conversion in sputum and is mandatory in some patients who are treated by second line drugs [36]. Quinolones have been studied as an alternative treatment for
4.2. Nontuberculous mycobacteria (NTM) NTM are ubiquitous organisms found in soil and water that can cause opportunistic infection in immunocompromised patients. Among SOT patients, lung transplant recipients are at higher risk of pleuropulmonary disease as a consequence of potent immunosuppression combined to underlying structural disease promoting airway colonisation [38]. [39] [40] In KTR, NTM can cause pneumonia though less frequently than cutaneous or disseminated presentation [41]. The diagnosis of pulmonary disease with NTM requires clinical, radiological and bacteriological criteria according to the American Thoracic Society [42]. Fever with persistent respiratory complaints will prompt a radiographic evaluation that can show nodular or cavitary opacities on chest X-ray or multifocal bronchiectasis with small nodules on CT scan (Fig. 3). Microbiology criteria include positive culture from respiratory specimens (2 consecutive sputa or one bronchoalveolar lavage) or from pulmonary tissue [42]. NTM grow slowly in culture, often delaying the diagnosis. Few cases of NTM pulmonary infection in KTR have been reported so far. Reviewing 14 published cases, Ho et al. identified 3 mycobacterial species mainly responsible for NTM pulmonary infections in KTR: Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium avium complex (MAC). The mean time from transplantation to onset of pulmonary disease was 33.4 months (2–120 months). Outcome was favorable in all patients but one [43].Risk factors for developing NTM pneumonia after renal transplant are not known. An underlying pulmonary disease could predispose to NTM colonisation or infection in patients under immunosuppression. NTM should be identified to the species level. Commercial DNA probes and high-performance liquid chromatography allow rapid species identification. Other techniques including extended antibiotic in vitro susceptibility testing, DNA sequencing or PCR restriction endonuclease assay may be necessary. ATS guidelines recommend a threedrug therapy in severe lung disease. The choice of antibiotics depends 92
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Conflicts of interest
on NTM species. For MAC pulmonary disease, the combination includes a macrolide (clarithromycin or azithromycin), rifampicin, and ethambutol. In a limited number of species only, the correlation between in vitro susceptibility testing and clinical outcome has been demonstrated. AFB smears and cultures of sputum must be collected monthly during therapy to assess response. A culture-negative status for 12 months while receiving the macrolide-containing regimen is required [42]. Reduction of immunosuppression must be considered. When treated adequately, the outcome of NTM lung disease is good [43].
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5. Rhodococcus equi Among SOT recipients, KTR are at highest risk for Rhodococcus equi infection. This zoonotic organism belongs to the aerobic Actinomycetes. It is a Gram-positive, aerobic bacterium that can exist as a coccus or a bacillus and is sometimes acid-fast. It is a facultative intracellular pathogen. Half of the infected patients report a history of exposure to farm soil or to animals. Inhalation of infected aerosols and dust particles seems to be the predominant route of disease transmission, but also inoculation into a wound or mucous membrane, or ingestion and passage through the alimentary tract has been suspected. Nosocomial cases of infection, as well as patient-to-patient transmission were also suspected [44]. In a review of 2012, infection with Rhodococcus occurred mostly in immunosuppressed transplant recipients receiving a triple therapy including steroids, azathioprine or mycophenolate and a CNI. The delay between transplantation and Rhodococcus pneumonia was 3 years (3 months-19 years) [45]. Generally the disease tends to follow a subacute course with progressive cough, pleuritic chest pain, and fever often accompanied by cachexia, weight loss and fatigue. Chest X-Ray and lung CT show necrotic pneumonia, nodules or cavitary lesions, enlargement of mediastinal lymph nodes and pleural effusion. The most common radiographic image is cavitary upper-lobe pneumonia [46]. Recurrent pneumothorax and invasion of contiguous chest structures were also described. In 82% of cases the lung is the sole site of infection. In 18% of the patients, extrapulmonary infections occur, predominantly subcutaneous abscesses, bone infection and CNS involvement. The bacteria can be isolated from blood cultures (25% of transplant recipients have a concomitant bacteremia). Culture of sputum is positive in only 20% and should be held for more than 48 h [45]. Often the diagnosis needs bronchoalveolar lavage or biopsy. The biopsy usually shows pulmonary malakoplakia characterised by a dense infiltration of foamy histiocytes with intracellular coccobacilli and Michaelis-Gutmann bodies [46]. Identification of this organism is difficult. The MALDI-TOF mass spectrometry can be use, but in several cases, identification required 16S rRNA gene-sequencing [47]. Treatment associates two or three antibiotics that should be chosen according to in vitro susceptibility testing and infection foci. No standardized treatment regimen exists. Intravenous treatment for a minimum of six weeks has been proposed, until clinical and radiological improvement, and continued orally for at least six months depending on infection size and site. The preferred oral regimen includes quinolones, tetracycline (minocycline being more frequently used among KTR), and rifampicin [44] [48]. Development of resistance during treatment has been reported [45]. Recurrence is a common problem in R. equi infection with acquired resistance [49]. If possible, the treatment should be completed by surgical resection and reduction of immunosuppressive treatment. 6. Conclusion Pneumonia caused by opportunistic bacterial pathogens can be lifethreatening in KTR. Prompt recognition of the involved microorganism is crucial for initiating antibiotherapy and determining treatment duration. Interactions with immunosuppressive therapy should be considered as well as reducing immunosuppression if necessary. 93
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