ARTICLE IN PRESS doi:10.1510/icvts.2007.171579
Interactive CardioVascular and Thoracic Surgery 7 (2008) 771–776 www.icvts.org
Institutional report - Thoracic general
Surgical treatment of pulmonary aspergillosisymycosis in immunocompromised patients Bernhard C. Dannera,1,*, Vassilios Didilisb,1, Hilmar Do ¨rgea, Dimitrios Mikroulisb, Georgios Bougioukasb, Friedrich A. Scho ¨ndubea Department of Thoracic, Heart and Vascular Surgery, Georg August University of Go ¨ ttingen, 37075 Go ¨ ttingen, Germany b Department of Cardiothoracic Surgery, Democritus University of Thrace, Alexandroupolis, Greece
a
Received 12 November 2007; received in revised form 26 March 2008; accepted 13 May 2008
Abstract Invasive pulmonary aspergillosis is a severe complication in immunosuppressed patients. Surgical resection can be curative in certain patients after antifungal treatment. Over a 7-year period, ten patients with suspected invasive pulmonary aspergillosis of two university hospitals were retrospectively reviewed. A literature review was undertaken. Patient’s age was 48.1 years (mean); the cause of immunosuppression was a hematological disease with consecutive therapy in seven patients and chronically corticoid therapy in three patients. After an antifungal therapy, surgical resection was performed with lobectomyysegmentectomy in 60% and with wedge-resection in 40%. Postoperative course were uneventful in seven patients, two patients died due to infectional circumstances, and one patient was reoperated because of empyema. The underlying disease marked long-term follow-up. Resection of focal pulmonary invasive aspergillosis can be curative. Clinical circumstances and dissemination must be taken into consideration to indicate surgery. To point out the best pathway randomised prospective studies are necessary. 䊚 2008 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Pulmonary aspergillosis; Thoracic surgery; Immunosuppression
1. Introduction Fungal infections of the lung are among the most feared infections in immunocompromised patients. Aspergillus is the most common ubiquitary pathogen affecting the lung. There are three main entities of infection with Aspergillus: (1) Pulmonary aspergilloma, which is associated with preexisting cavities, (2) The allergic bronchopulmonary aspergillosis (APBA), which is an immunoreaction of the lung to the allergen and (3) Invasive aspergillosis, affecting all organs and particularly the lung (invasive pulmonary aspergillosis: IPA). The underlying disease in surgical resection of pulmonary aspergilloma is often an old history of tuberculosis or lung abscess in 65–79% of cases. IPA is a severe complication in immunocompromised or neutropenic patients. In cases of bone marrow transplantation, the incidence of invasive pulmonary aspergillosis is about 5% with an mortality rate up to 82% despite antifungal treatment w1x. In the last decades the incidence of IPA arose especially in immunocompromised patients. In an autopsy series in Germany w2x, the prevalence of Aspergillus infection increased from 0.4% in the 1980s up to 3.1% in the 1990s. 1 Both authors contributed equally to this work. * Corresponding author. Tel.: q49-551-39-6061y39-6008; fax: q49-551-396002. E-mail address:
[email protected] (B.C. Danner).
䊚 2008 Published by European Association for Cardio-Thoracic Surgery
Solitary lung organ involvement was seen in 45%, whereas in disseminated Aspergillus infection the lung was involved in 92%. The evidence grade in the optimal treatment of the infection of the lung with invasive Aspergillus remains low. Whereas in cases of pulmonary aspergilloma resection is recommended, in immunosuppressed patients indication for surgical resection is more complex. We reviewed clinical data of patients in two university hospitals who had surgery for lung resection with suspected invasive pulmonary Aspergillus. 2. Patients and method Over a seven-year period (2001–2007) patients who were suspected of having invasive pulmonary aspergillosis and have had thoracic surgery, formed the basis of this study. In a retrospective manner we reviewed the dossiers of ten patients treated at the Department of Thoracic, Heart and Vascular Surgery of the University Hospital Go ¨ttingen, Germany and the Department of Cardiothoracic Surgery of the University Hospital Alexandroupolis, Greece; five in each institution. Preoperative and postoperative data were collected, radiological results were reviewed and follow-up of the patients course were taken. A literature review over the last 12 years was undertaken to compare indication to surgery, surgical results and follow-up.
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3. Results Patient’s age was 48.1 years (mean) in a range from 18.4 to 68.3 years. Eight patients were male, two patients female. Underlying disease was in six patients acute leukaemia with pre or post bone marrow transplantation in four patients. One patient had a non-Hodgkin’s lymphoma and the other three patients were chronically immunosuppressed with corticosteroid and an additional immunosuppressive medicament. In two of them no neutropenia was observed. Radiological signs and clinical findings suspected invasive pulmonary aspergillosis. One patient (not shown) was referred from surgery due to disseminated aspergillosis and was treated medically. Diagnosis was made in all patients on clinical signs, in combination with typical radiological signs like the earlier ‘halo’ (Fig. 1) or the later ‘air crescent’ sign (Fig. 2) on thoracic CT and with regard to laboratory findings w3x. Bronchioalveolar lavage (BAL) findings or antigen testing were inconstant. In patients 3, 6, 7 and 8 there was a positive BAL or antigen test; the other patients had a negative testing. After diagnosis nine patients were treated with antifungal medication (2 with Amphotericin B, 4 with voriconazole and 3 with initial therapy of Amphotericin B which was changed to voriconazole) and after a period of up to seven months (mean 2.4 months) surgical intervention was performed. In one patient the operation they underwent was urgent because of persistent haemoptysis without a longer period of antifungal treatment. Preoperative data are shown in Table 1. The opacities were found in seven patients in the upper lobes, the lower lobes were involved in two patients, and the middle lobe was affected in one patient. Operative resection was done either with wedge resectionysegmentectomy in four patients or with lobectomy in six patients. In two patients more than one wedge-resectionysegmentectomy was necessary. Postoperative course was uneventful in six patients and they were discharged from the surgical department after a mean time of 7.8 days. Complications: in one patient (patient 2) a psycho syndrome with exclusion of neuroaspergillosis was diagnosed; he was discharged after
Fig. 1. Halo sign – a mass-like infiltrate with a surrounding halo of ground glass attenuation.
Fig. 2. Air crescent sign – a pulmonary cavitation.
11 days. In two patients septic or consecutive conditions occurred: patient no. 4 died due to fulminate pseudomonas pneumonia without recurrence of Aspergillus, and patient no. 9 died due to multiorgan failure. One patient (no. 3) was reoperated because of pleural empyema and completion lobectomy was done; he was discharged after 36 days. Postoperative histopathology revealed Aspergillus hyphae (ascomycetes)in 4 patients (see Fig. 3). In two patients another fungal pathogen was detected: urediniomycetes (Sporobolomyces salmonicolor) in patient 5 and zygomycetes in patient 9. In four patients no more typical hyphae were found and histopathology revealed necrosis and abscess formation with multinuclear giant cells of Langhans or foreign body type, respectively. In three of these four patients, preoperative BAL or antigen findings were positive for Aspergillus, so that aspergillosis was very probable. Longer follow-up was marked by the underlying disease: patients with leukaemia or haematological disease had a
Fig. 3. Aspergillus hyphae – stain, periodic acid-Schiff, original magnification =400.
43.9ymale 68.3ymale 62.8ymale 36.0ymale
39.8yfemale 38.9yfemale
44.2ymale 68.4ymale
59.9ymale
2 3 4 5
6 7
8 9
10
2 months
7 months
1 month
2 months 5 months 2 months
2.5 months 1 month 7 days 1.5 months
2
3
4 5 6
7 8 9 10
Time from diagnosis to operation
1
Patient no.
Wedge left upper Lobectomy left upper Segmentectomy 1q2 left upper Lobectomy, left upper Lobectomy, right upper Wedge, right lower Lobectomy, right middle
Segmentectomy and wedge, right upper
Lobectomy, left lower
Wedge right upper
Operation
AML
AML NHL
M. Crohn Type A Nephritis Liver TX MDSyAML and bone marrow transplantation AML ALL
ALL
Underlying disease
Table 2 Intraoperative and postoperative data
18.5ymale
Ageysex
1
Patient no.
Table 1 Preoperative data
None None Respiratory insufficiency, death None
Psycho syndrome (no neuro-aspergillosis) Empyema and reoperation (24.po) with lobectomy right upper Sepsis, death None None
None
Complications
90yml
90yml 190yml
110yml 100yml
none 700yml none 700yml
200yml
Neutropenia
14 days 7 days 8 days continuing of haematological therapy 9 days 9 days 2 months 9 days
36 days
11 days
5 days
Discharge of surgical department
Cytarabine, Idarubicine Cyclophosphamide, Vincristine, Adriamycine, Dexamethosone (Hyper-CVAD) Cytarabine, Idarubicine Cyclophosphamide, doxorubicin, oncovine, prednisolone (CHOP) IdarubicineqFludarabineqAracytine
CorticoidqSulfasalazin CorticoidqCyclophosfamide CorticoidqTacrolimus TacrolimusqMycophenolatmophetil
GMALL protocol 7y2003
Immunosuppression
6.5 months 19 months 2 months 2 months
14 days 2 months 6 months
10 months
24 months
3 months
Follow-up
‘halo-’ sign
‘air crescent’ sign ‘halo-’ sign
‘air crescent’ sign ‘air crescent’ sign
Initial ‘halo’, later ‘air-crescent’ sign ‘air-crescent’ sign ‘air-crescent’ sign ‘halo’ sign ‘air crescent’ sign
CT-findings
Death, leukaemia and BMT Alive, BMT Death, sepsis Alive, reinductionchemotherapy
Alive, reinductionchemotherapy Alive, continuing corticoid Death, fasciitis of the limb (arterial insufficiency) Death, sepsis Death, ReBMT, GvHD Death, leukaemia and BMT
Outcome; cause
Voriconazole None, directly operated due to haemoptysis Initial Amphotericin B, later Voriconazole
Voriconazole, Cotrimoxazole, Aciclovir Amphotericin B, monaldi drainage Amphotericin B Voriconazole, Cefepime, Tobramycine Initial Amphotericin B, later Voriconazole Voriconazole Amphotericin BqCaspofungin, later voriconazole
Initial antifungal therapy
Aspergillus Hyphae (Sporobolomyces salmonicolor) No hyphae (necrosis and abscess) (necrosis and abscess) No hyphae (necrosis and abscess) No hyphae (necrosis and abscess) Zygomycetes Aspergillus
Aspergillus
Aspergillus
No hyphae
Diagnosis
04y2007
05y2004 05y2002
07y2004 11y2003
05y2004 02y2001 11y2005 10y2005
10y2006
Onset and symptoms
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very poor prognosis. Three out of six patients died after a median follow-up of 6.4 months. In all patients, reinduction chemotherapy or bone marrow transplantation after lung operation was introduced. In the patient group with corticoid immunosuppression, one patient (patient 3) died due to fulminate fasciitis of the limb because of peripheral arteriosclerosis after 10 months. The intraoperative and postoperative data are shown in Table 2. 4. Discussion Pulmonary aspergilloma occurs mostly in patients with tuberculosis or lung abscess (up to 80%) and surgical intervention has a low perioperative mortality of 0% in simple aspergilloma (thin wall cavitation) up to 5.6% in complex aspergilloma (thick wall cavitation). In countries without high prevalence of tuberculosis, pulmonary aspergilloma is not as frequent as in other countries. Invasive pulmonary aspergilloma is a severe complication mostly in patients with immunosuppressive therapy or immunocompromised status, i.e. chemotherapy, bone marrow or stem-cell transplantation, organ transplantation, autoimmune disease, leukaemia and solid tumours or in acquired immunodeficiency w1, 3x. The increase of these therapies rises the incidence of invasive pulmonary aspergilloma w2x. The diagnosis of invasive aspergilloma which affects mostly the lung w3x, could be difficult as up to one third of patients have no early clinical signs. Progressive fever and cough are early signs but unspecific. Pneumothorax could appear and chest pain could suggest invasive pulmonary aspergillosis w1, 3x. Thoracic CT-scan is an essential tool for diagnosis. Mostly there are typical signs like the early ‘halo’ sign, which is highly specific for IPA but disappears after about 14 days. The later ‘crescent air’ sign, which suspect invasive pulmonary aspergillosis is not as specific as the ‘halo’ sign w4x. BAL findings or other laboratory tests are not very sensitive w3x; open lung biopsy could be a further diagnostic tool. In our patient group diagnosis was made by recurrent CTscans and clinical course. BAL or antigen testing was only in 40% positive. Haemoptysis was seen in 40% as a clinical sign. All patients received immunosuppressive treatment; however, three patients had a non-haematological disease. Three out of nine patients were treated with Amphotericin B and in recent years with voriconazole. Amphotericin B was the standard treatment w3x. In one patient we saw a negative adverse effect: he developed a deep venous thrombosis and renal failure with consecutive dialysis. In recent years the standard treatment is application of voriconazole intravenously, which is more effective than Amphotericin B and has lesser adverse events w5x. Surgical intervention in general is indicated in haemoptysis and in persistence of the radiological signs suggesting a persistence of the invasive aspergillosis cavities. Because of persistent intracavitary fungal growth the risk of relapse of IPA is high under neutropenia or immunosuppression. In our series the operation was done before recurrence of neutropenia. All patients survived the initial surgical procedure. In one patient an incomplete resection (patient 3)
provoked a pleural empyema, which was resolved with completion lobectomy. Extensive lung resection surgery such as pneumectomy could be avoided in all cases, just as thoracoplastic procedures without negative effect. Despite the fact that there is a lack of correct diagnosis, some authors recommend an aggressive surgical approach with resection in suspecting invasive pulmonary aspergillosis w6x. Surgical lung biopsies could be an option, but we do not recommend this approach because of the possibility of Aspergillus dissemination in the pleura, which we saw in one patient with consecutive postoperative empyema and the need for reoperation. In our series, suspicion of fungal infection was confirmed by histopathology in 60% of the cases, whereas in 20% other fungi than Aspergillus were found. In the results of literature review, Aspergillus identification ranges from 40–100% (Table 3). Animal models raise controversial results: in neutropenic rats with incubated lung of aspergillosis lung resection was without any benefit on survival of the rats. Origin of immunosuppression revealed very different outcomes: in rabbits there was a high difference between granulocytopenia, which was associated with a higher mortality rate than in immunosuppression due to prednisolone, whereas cyclosporine was not as immunosuppressive w7x. Clinically, immunosuppression by corticosteroids could have even fatal effects in patients with COPD and Aspergillus infection with a very high mortality rate. Nevertheless, there is no randomised, prospective trial for optimised treatment, including the antifungal and surgical approach. In a disease with progressive or stable radiological findings under antifungal treatment, or the need for further immunosuppressive treatment and lack of dissemination, surgical resection may be curative and useful. This includes the fact that pulmonary cavities are focally localised. Furthermore, the clinical status including the functional operability and the underlying disease of the patient are predisposing factors to indicate surgical intervention and for long-term follow-up. In our series, patients with haematological disease have a poor long-term survival (median 6.4 months), whereas in patients with non-haematological disease they have a better long-term survival (11 months). We overviewed the literature of the last 12 years. Essential data of these studies are shown in Table 3. Cumulative mortality (30-day) and morbidity of these 198 patients was 12.6% (range 0–31.2%) and 12.7% (range 7.6–18.5%), respectively. Operative procedure was pneumectomy in 4.0%, lobectomy in 66.2% and wedge resection in 28.8%. Only in one institution enucleating technique (1%) was performed w8x. Histological findings confirmed Aspergillus in 77.8% (range 40–100%) which indicates the difficulties in preoperative diagnosis or the bias of retrospective analysis. These results are comparable with our findings. Remarkable is that over this 25-year period only 7.9 patients per year were operated in all institutions. Each institution has had an operation incidence of 1–2.5 patients per year (mean 1.75 patientsyyear). In conclusion, IPA or lung mycosis is a severe complication of immunosuppressive therapy or in immunocompromised patients with a near 100% mortality without treatment.
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Table 3 Literature review Patients (n)
Period
Underlying disease (%)
Operative procedure (%)
Operative mortality/ morbidity (%)
Histology for aspergillus (%)
Author
16
1987–1993 (7 years) 1988–1997 (9.4 years) 1988–1996 (9 years) 1983–1997 (15 years) 1986–1996 (10 years) 1988–1998 (10 years) 1982–1995 (13.8 years) 1991–2000 (10 years) 1983–2002 (20 years) 2001–2007 (7 years) 1983–2007 (25 years)
AML (31), (N)HL (38), LTX (13) AML (95)
P (12.5), L (62,5) W (25) L (53), W (47)
31.2y12.5
56.3
Robinson et al., 1995 w9x
6.7y13.2
100
Bernard et al., 1997 w10x
AML (72), ALL (16)
P (5.6), L (61.1), W (33.3) L (74), W (26)
0yunknown
66.6
Baron et al., 1998 w6x
7.4y18.5
81.5
L (23); W (77)
7.6y7.6
n.g.
Reichenberger et al., 1998 w11x Salerno et al., 1998 w12x
P (7.6), L (30.8), W (61.6) P (11), L (89)
15.3y15.3
76
Pidhorecky et al., 2000 w13x
22.8y11.4
100
Yeghen et al., 2000 w14x
L (80), W (20)
0y20
40
Al Kattan et al., 2001 w15x
L (56), W (39), E (5) L (60), W (40)
10y10
75.6 ‘fungal’
Matt et al., 2003 w8x
20y10
60
Our series
12.6y12.7
77.8
Cumulative
15 18 27 13 13 35 10 (subgroup) 41 10 Total: 198
AML (40), ALL (15), AA (26) AML (46), ALL (23) AML (46), ALL (23) n.g., all patients received BMT AML (60), ALL (30) AyCML (66), AA (17), NHL (5) AML (40), ALL (20), LTx (10), NHL (10)
P: 4.0 L: 66.2 W: 28.8 E: 1
AyCML, acuteychronic myeloid leukaemia; ALL, acute lymphoblastic leukaemia; (N)HL, (Non) Hodgkin lymphoma; AA, aplastic anaemia; BMT, bone marrow transplantation; LTx, liver transplantation; P, pneumectomy; L, lobectomy; W, wedge resectionysegmentecomy; E, enucleation; n.g., not given; po, postoperative.
Standard treatment is antifungal chemotherapy and recovery of immunocompetence. In cases of haemoptysis or in pulmonary high risk region for haemoptysis (i.e. affecting great vessels) surgery is recommended. In a more focallike form surgical resection is probably definitive and curative. In cases necessary for further immunosuppressive treatment the resection is suggested. In our institutions we could recommend the following pathway: 1. Antifungal treatment pre- and postoperative until the clinical symptoms are improved. 2. In cases of a. persistent radiological findings and continuing immunosuppressive therapy b. symptoms like haemoptysis c. critical anatomical location of the cavitations d. progressive radiological findings despite antifungal therapy e. focal location of cavities surgical treatment is indicated. 3. In cases of surgery curative and definitive but lungsparing resection should be done. Lobectomy could be performed, but pneumectomy should be avoided. 4. No surgery should be indicated in cases of disseminated disease or a curative resection is not feasible In these cases, the operative mortality and morbidity remains low and is marked by the underlying disease. In diffuse affection of the lung, the surgical approach is associated with a worsening postoperative course and
relapse of infection. Further studies (randomised, prospective and multicentre) are required to determine the ranking of the surgical procedure in invasive pulmonary aspergillosis, also considering the immunosuppressive context. References w1x Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26:781–803. w2x Groll AH, Shah PM, Mentzel C, Schneider M, Just-Nuebling G, Huebner K. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996;33:23–32. w3x Stevens DA, Kan VL, Judson MA, Morrison VA, Dummer S, Denning DW, Bennett JE, Walsh TJ, Patterson TF, Pankey GA. Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America. Clin Infect Dis 2000;30:696–709. w4x Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, Lopez J, Couillault G, Piard F, Vagner O, Guy H. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoraciccomputed tomography scans in patients with neutropenia. J Clin Oncol 2001;19:253–259. w5x Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–415. w6x Baron O, Guillaume B, Moreau P, Germaud P, Despins P, De Lajartre AY, Michaud JL. Aggressive surgical management in localized pulmonary mycotic and nonmycotic infections for neutropenic patients with acute leukemia: report of eighteen cases. J Thorac Cardiovasc Surg 1998; 115:63–68. w7x Berenguer J, Allende MC, Lee JW, Garrett K, Lyman C, Ali NM, Bacher J, Pizzo PA, Walsh TJ. Pathogenesis of pulmonary aspergillosis. Granulocytopenia versus cyclosporine and methylprednisolone-induced immunosuppression. Am J Respir Crit Care Med 1995;152:1079–1086. w8x Matt P, Bernet F, Habicht J, Gambazzi F, Passweg J, Gratwohl A, Tamm M, Zerkowski HR. Short- and long-term outcome after lung resection
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w9 x
w10x
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B.C. Danner et al. / Interactive CardioVascular and Thoracic Surgery 7 (2008) 771–776 for invasive pulmonary aspergillosis. Thorac Cardiovasc Surg 2003;51: 221–225. Robinson LA, Reed EC, Galbraith TA, Alonso A, Moulton AL, Fleming WH. Pulmonary resection for invasive Aspergillus infections in immunocompromised patients. J Thorac Cardiovasc Surg 1995;109:1182– 1196. Bernard A, Caillot D, Couaillier JF, Casasnovas O, Guy H, Favre JP. Surgical management of invasive pulmonary aspergillosis in neutropenic patients. Ann Thorac Surg 1997;64:1441–1447. Reichenberger F, Habicht J, Kaim A, Dalquen P, Bernet F, Schlapfer R, Stulz P, Perruchoud AP, Tichelli A, Gratwohl A, Tamm M. Lung resection for invasive pulmonary aspergillosis in neutropenic patients with hematologic diseases. Am J Respir Crit Care Med 1998;158:885–890.
w12x Salerno CT, Ouyang DW, Pederson TS, Larson DM, Shake JP, Johnson EM, Maddaus MA. Surgical therapy for pulmonary aspergillosis in immunocompromised patients. Ann Thorac Surg 1998;65:1415–1419. w13x Pidhorecky I, Urschel J, Anderson T. Resection of invasive pulmonary aspergillosis in immunocompromised patients. Ann Surg Oncol 2000; 7:312–317. w14x Yeghen T, Kibbler CC, Prentice HG, Berger LA, Wallesby RK, McWhinney PH, Lampe FC, Gillespie S. Management of invasive pulmonary aspergillosis in hematology patients: a review of 87 consecutive cases at a single institution. Clin Infect Dis 2000;31:859–868. w15x Al Kattan K, Ashour M, Hajjar W, Salah ED, Fouda M, Al Bakry A. Surgery for pulmonary aspergilloma in post-tuberculous vs. immuno-compromised patients. Eur J Cardiothorac Surg 2001;20:728–733.
