Pulmonary resection for fungal infection in children undergoing bone marrow transplantation

Pulmonary resection for fungal infection in children undergoing bone marrow transplantation Recipients of bone marrow transplants for hematologic malignancies are at risk for a variety of infectious complications. We have reviewed our experience with six patients 2 to 15 years of age who developed significant fungal infections of the lungs before or after bone marrow transplant. No patient was known to have active fungal or bacterial infection at the time bone marrow transplant was performed. In two patients fungal infections were diagnosed before bone marrow transplant, and operations were performed to permit bone marrow transplant under optimal conditions. Four patients had pulmonary mycoses discovered after bone marrow transplant, and underwent operation 12 to 24 days following transplant. Operations consisted of lobectomy (three), multiple unilateral wedge resections (one), staged segmentectomy and contralateral wedge resection (one), and staged bilateral wedge resection (one). Survival following bone marrow transplant was achieved for 6 months and 11 months in patients undergoing lung resection before transplant, and for 24, 30, 39, and 60 days in patients undergoing lung resections after transplant. Bone marrow transplant recipients are at high risk of pulmonary mycoses, and a vigorous search for occult fungal infections should be carried out before transplant. Aggressive operative treatment of fungal infections of the lungs combined with antifungal chemotherapy before transplant may offer the best hope of extended survival. (J THORAC CARDIOVASC SURG 1992;104:684-7)

Flavian M. Lupinetti, MD, Douglas M. Behrendt, MD, Roger H. Giller, MD, Michael E. Trigg, MD, and Pedro de Alarcon, MD, Iowa City, Iowa

Patients with hematologic malignancies requiring bone marrow transplantation (BMT) are at risk for numerous infectious complications.F' The respiratory system is particularly susceptible to such infections, and among the most devastating infections are the pulmonary mycoses.v? Fungal infections of the lungs in patients requiring BMT are frequently fatal, and optimal management of these difficult problems remains undefined. Thoracic surgeons most commonly encounter pulmonary mycoses in the nonimmunosuppressed patient, for whom operative intervention may be rarely indicated. In contrast, our recent experience suggests that the role of operative

From theDepartment ofSurgery, Division ofCardiothoracic Surgery, Department ofPediatrics, Pediatric Bone Marrow Transplant Program, TheUniversity ofIowa School ofMedicine, Iowa City, Iowa. Received for publication Dec. 18, 1990. Accepted for publication Oct. 28, 1991. Address for reprints: Flavian M. Lupinetti, MD, University of Michigan Hospital, Section ofThoracic Surgery, 2120 Taubman Center, Box 0344, Ann Arbor, MI 48109. 12/1/35158

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intervention in BMT patients with fungal pneumonitis should be reexamined. We report our experience with six pediatric patients with leukemias who underwent BMT and who developed fungal infections of the lungs before or after marrow transplant. Each patient was treated with pulmonary resection and antifungal chemotherapy in an attempt to eradicate the infection. Clinical material The medical records of all pediatric BMT patients at the University of Iowa Hospitals and Clinics were reviewed. The records ofthose whounderwent pulmonary resection for fungal infections were examined for pertinent clinical and microbiologic data. These data are summarized in Table I. Six patients, three boys and three girls, form the basisof this study. Diagnoses were acute lymphocytic leukemia in two patients, acute lymphoblastic leukemia in two, acute nonlymphocytic leukemia in one,and chronicmyelogenous leukemia in one. Age at the time of diagnosis of leukemia ranged from 7 monthsto 15 years. All patients required BMT following failure of chemotherapy for leukemia. Initial marrow transplant successfully resulted in goodengraftment, as assessed by blood counts and marrow karyotyping in five patients. One patient required a second transplant,but alsoultimately demonstrated goodengraftment.

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Table I Patient No.

Age.* sex

4 yr, M

2

15 yr, F

Diagnosis

Acute lymphoblastic leukemia Acute lymphocytic leukemia

Operation

Operation before/after transplant

A. glaucus

RUL wedge resection

After

60 days

Fusarium sp.

Recurrent leukemia

Before

322 days

CMV

Fungal infection

3

7mo, M

Acute lymphocytic leukemia

Ac ftuvus

4

9 yr, M

Chronic myelogenous

A·fiavus

RUL segmentectomy; LLL wedge resections (staged) LLL wedge resections; RUL wedge resections (staged) LUL lobectomy

A. sp. A·fiavus

5

II yr, F

6

12 yr, F

leukemia Acute nonlymphocytic leukemia Acute lymphoblastic leukemia

Survival after transplant

Cause of death

pneumonia Before

194 days

CNS leukemia

After

30 days

CNS fungus

RUL lobectomy

After

39 days

CNS fungus

RLL lobectomy

After

24 days

Fungal pneumonia

A. Aspergillus; LLL.LUL. left lower lobe. left upper lobe; RLL, RUL, right lower lobe, right upper lobe; CMV, cytomegalovirus; CNS, central nervous system.

*At

time of diagnosis of leukemia

Pulmonary mycoses were diagnosed by characteristic radiographic findings of spherical intrapulmonary lesionsand sputum cultures or by smears positive for fungus. Bronchoscopy was performed in some cases as part of the initial evaluation and in all patients at the time of operation. Amphotericin B therapy was initiated at the time the presence of fungal disease was suspected and was continued through the postoperative period. Operations were performed in all cases with the intention of achieving local control of the infection. An additional indication in one patient was a single episode of hemoptysis. Two patients developed pulmonary mycoses and underwent lung resection during evaluation for marrow transplant, and transplant was delayed until there was no evidence of residual infection. The first patient, who has been reported previously," developed Fusarium infection involving both lungs. The patient underwent posterior segmentectomy of the right upper lobe, followed 3 weeks later by multiple wedge resections of the left lower lobe. All specimens contained Fusarium. Amphotericin B was initiated preoperatively and was continued until after the second operation. The second patient developed Aspergillus infection of the skin, nasal cavity, and both lungs. Bilateral, staged, wedge resections of both lungs were performed 4 days apart. This patient also received amphotericin B beginning before the first operation. Each of these two patients received successful BMTs 2 months following their second operations. Four patients developed fungal infections of the lungs after BMT, although none was known to be infected before transplantation was performed. Each patient was shown by culture results and histologic examination of resected specimens to have Aspergillus. Amphotericin B was started at the time fungal infection was suspected and was continued throughout the postoperative period. Operations in this group of patients consisted of right upper lobe wedge resection, left upper lobectomy, right upper lobectomy, and right lower lobectomy, respectively, performed 12 to 24 days after marrow transplant. All patients eventually succumbed to their underlying disease or to complications of treatment. The two patients who underwent pulmonary resection and antifungal chemotherapy before marrow transplant died 322 days and 194 days following trans-

plant. The causes of death were cytomegalovirus pneumonia and central nervous system leukemia, respectively. Neither patient developed any evidence of pulmonary or extrapulmonary fungus at any time following completion of antifungal treatment. The duration of survival was considerably shorter in the four patients who developed pulmonary mycoses following BMT. These patients survived 24 to 60 days following transplant. One death was the result of recurrent leukemia, two deaths were attributed to central nervous system fungal infection, and one death was from progressive fungal pneumonitis. In summary, combined treatment of pulmonary mycoses with antifungal chemotherapy and lung resection achieved local control of the infection in five.of six patients. Two of these patients, however, had proven or suspected central nervous system fungal infections that were thought to be important factors in these patients' deaths.

Discussion Pulmonary infections are the most common complication of BMT. 5 The importance of pulmonary infections in the BMT recipient may not be fully appreciated even by those familiar with management of solid organ transplant recipients. The recipient of allogeneic bone marrow requires preconditioning to ablate host immune defenses and thereby permit marrow engraftment. This is fundamentally different from the recipient of a heart or lung transplant, whose immune defenses are therapeutically suppressed but not eliminated. Marrow recipients are at risk for the development of exogenous infections as well as for reactivation of endogenous infections. Cytomegalovirus is the most common pulmonary pathogen following BMT. Until recently, when more effective antiviral agents became available, cytomegalovirus pneumonia was fatal in approximately

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90% of cases." Bacterial and fungal pulmonary infections each affect 20% to 50% of BMT patients.' Pulmonary mycoses following marrow transplant is fatal in approximately 80% of cases, and thus may carry a mortality exceeding that of bacteria or viruses.':5, 8 A majority of patients affected by fungal disease will have multisystem involvement. 8 Among the factors that may contribute to the predilection of marrow transplant recipients to opportunistic mycoses are damage to the mucocutaneous barriers to fungi (by chemotherapy, radiation, intravenous catheters, and graft-versus-host disease), impaired humoral immunity (caused by lymphoid disease, splenic dysfunction, and side effects of therapy), impaired cellular immunity (resulting from neutropenia, cytotoxic drugs, and other causes), and loss of resistance to colonization (related to use of prophylactic or therapeutic antibiotics]," In the initial period following marrow transplant, neutropenia and disruption of anatomic barriers are the most important contributors to the development of fungal infection, whereas in the later posttransplant period the slow reconstitution of lymphoid immunity and the presence of graft-versus-host disease are the more powerful influences on susceptibility to infection.' Aspergillus and Candida are the most common fungal pathogens following marrow transplant.I'l II Because these are respiratory pathogens, the lung and sinuses are the most frequent sites of Aspergillus infection in immunosuppressed patients. Laminar airflow isolation appears to be the only effective prophylactic measure to prevent fungal infection in BMT patients.V Prevention of fungal infections with antifungal chemotherapy alone is often unsuccessful. Oral polyenes, such as nystatin, are not well absorbed from the gastrointestinal tract, and therefore do not protect the airways." Ketoconazole and fluconazole are not effective against Aspergillus. Ketaconazole in fact has an antagonistic effect on the antifungal activity of amphotericin Band may reduce the susceptibility offungi to the latter agent.l ' Itraconazole, a drug related to ketoconazole, has been reported to be effective in treating aspergillosis, although its use in BMT patients has not been reported. 14 The use of immunoglobulin has also been reported to reduce the incidence of bacterial as well as fungal infection following marrow transplant.P Amphotericin B remains the cornerstone of pharmacologic treatment of mycotic infection despite its considerable toxicity. However, amphotericin B administered systemically is not well distributed into the sputum.f Nebulized amphotericin B may diminish the frequency of invasive aspergillosis in BMT recipients as well as in other granulocytopenic patients. The benefits of this treat-

The Journal of Thoracic and Cardiovascular Surgery

ment may not be as marked in patients hospitalized in rooms with laminar air flow and high efficiency air filtration.'" The characteristic rounded infiltrates on chest roentgenogram should be cause for suspicion of aspergillosis, and should dictate appropriate confirmatory studies in candidates for marrow transplantation. However, Aspergillus remains difficult to diagnose early in the clinical course. Sputum cultures may be negative for Aspergillus despite established infection.'? Delay of treatment beyond 2 weeks may be uniformly fatal. 18 It is therefore appropriate to institute amphotericin B therapy in the neutropenic patient who remains febrile despite the administration of multiple antibacterial drugs." 19 In any group of patients such as this, all of whom had an ultimately fatal course, the merits of the treatment undertaken remain debatable. These results must be placed in the context of the underlying disease. BMT for acute lymphocytic leukemia results in a 30% to 60% 2-year disease-free survival when performed at the optimal time-i.e., during the first remission. Two-year survival may be as low as 15% when marrow transplant is performed during a relapse.' Despite the eventual deaths of all patients in this series, we believe there are important conclusions that can be drawn from this brief experience. First, treatment of pulmonary fungal infections is more likely to be successful if employed before marrow transplantation. The best survival was obtained in the two patients who benefitted from pretransplant diagnosis, antifungal chemotherapy, and resection. In neither patient did any fungal infection recur following transplant, and both died from other causes consistent with their underlying disease. In order for future patients to receive the benefits of such treatment, the diagnosis of fungal infection must be suspected early. Careful examination of the patient for the cutaneous and pulmonary manifestations must be pursued, and the appropriate radiologic studies must be performed. The second conclusion that may be appropriate is that resection and antifungal chemotherapy provide local control of established pulmonary fungal infections in this immunosuppressed population. In only one patient reported herein did fungal infection progress in the lungs following resection. However, two patients went on to develop and die from central nervous system mycoses. It is possible that more prompt resection of the infected tissue may prevent the spread of the infection. The role of pulmonary resection for fungal disease is relatively limited in the patient with normal immune defenses. Aspergillomas in nonimmunosuppressed patients remain asymptomatic or may on occasion spontaneously regress. The profoundly immunosuppressed

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patient is unlikely to have a favorable spontaneous resolution of such a lesion. Therefore we suggest that the indications for resectional treatment combined with antifungal chemotherapy should be broadened for BMT recipients. We advocate complete resection of the fungal lesion, along with excision of sufficient normal tissue to prevent contamination of uninfected lung. This should be performed whenever the classic radiographic finding is discovered, and should not await positive cultures or other confirmatory tests. Our experience suggests that this can often be accomplished with a conservative resection, such as a wedge resection or segmentectomy, although a lobectomy may sometimes be necessary. REFERENCES 1. Winston DJ, Gale RP, Meyer DV, Young LS, UCLA Bone Marrow Transplantation group. Infectious complications of human bone marrow transplantation. Medicine 1979; 58:1-31. 2. van der Meer JWM, Guiot HFL, van den Broek PJ, van Furth R. Infections in bone marrow transplant recipients. Semin HematoI1984;21:123-40. 3. Meyers JD.lnfection in bone marrow transplant recipients. Am J Med 1986;81(suppllA):27-38. 4. Cordonnier C, Bernaudin J-F, Bierling P, Huet Y, Vernant J-P. Pulmonary complications occurring after allogeneic bone marrow transplantation. A study of 130 consecutive transplanted patients. Cancer 1986;58:1047-54. 5. Krowka MJ, Rosenow EC III, Hoagland He. Pulmonary complications of bone marrow transplantation. Chest 1985;87:237-46. 6. Lupinetti FM, Giller RH, Trigg ME. Operative treatment of Fusarium fungal infection of the lung. Ann Thorac Surg 1990;49:991-2. 7. Meyers JD, Flournoy N, Thomas ED. Nonbacterial pneu-

Fungal irifections in bone marrow transplant 6 8 7

monia after allogeneic marrow transplantation: a reviewof ten years' experience. Rev Infect Dis 1982;4:1119-32. 8. Watson JG. Problems of infection after bone marrow transplantation. J Clin Pathol 1983;36:683-92. 9. Milliken ST, Powles RL. Antifungal prophylaxis in bone marrow transplantation. Rev Infect Dis 1990;12(suppl 3):S374-9. 10. Hart PD, Russell E Jr, Remington JS. The compromised host and infection. II. Deep fungal infection. J Infect Dis 1969;120:169-91. 11. Ho WG, Winston DJ. Infection and transfusion therapy in acute leukaemia. Clin HaematoI1986;15:873-904. 12. Buckner CD, Clift RA, Sanders JE, et al. Protective environment for marrow transplant recipients. A prospective study. Ann Intern Med 1978;89:893-901. 13. Schaffner A, Frick PG. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J Infect Dis 1985;151:902-10. 14. Viviani MA, Tortorano AM, Langer M, et al. Experience with itraconazole in cryptococcosis and aspergillosis. J Infection 1989;18:151-65. 15. Tutschka PJ, Copelan EA, Kapoor N. Experience with intravenous immunoglobulins (IVIG) in BMT. In: Proceedings of the 22nd Congress of the International Society of Hematology. New York: Greene & Stratton, 1988:37. 16. Conneally E, Cafferkey MT, Daly PA, Keane CT, McCann SR. Nebulized amphotericin B as prophylaxis against invasive aspergillosis in granulocytopenic patients. Bone Marrow Transplant 1990;5:403-6. 17. Bodey GP. Infection in cancer patients. A continuing association. Am J Med 1986;81(suppIIA):11-26. 18. Aisner J, SchimpffSC, Wiernik PH. Treatment of invasive aspergillosis: relation of early diagnosis and treatment to response. Ann Intern Med 1977;86:539-43. 19. Meyers JD, Atkinson K. Infection in bone marrow transplantation. Clin Haematol 1983;12:791-811.