Pneumonia in Allogeneic and Autologous Bone Marrow Recipients

Pneumonia in Allogeneic and Autologous Bone Marrow Recipients* A Retrospective Study Giuseppe Gentile, :\f. D.; Alessandra .\lico::.::.i, M.D.; Corrado Ginnenia, M.D.; Anna Paola Iori, M.D.; Pierpaolo Petasecca Donati, M.Sc.; Saveria Capria, M.D .; and Pietro Martino, M.D. Pulmonary infections, which frequently occur during the early and late period following bone marrow transplantation for hematologic malignancies, are associated with significant morbidity and mortality. In this study the incidence, the infectious causes of pneumonia and the mortality related to pneumonia in 130 allogeneic and 290 autologous bone marrow recipients are reviewed. Both the incidence and the mortality by pneumonia were far lower in autologous

than in allogeneic bone marrow recipients. (Chest 1993; 104:371-75)

bone marrow transplantation (ALBMT) represents a potentially curative procedure for several hematologic malignancies, but the lack ofHLAidentical marrow donors limits its wider application. Autologous bone marrow transplantation (ABMT) has the advantage of avoiding a lack of donor availability and problems related with graft-vs-host disease (GVHD). Pulmonary complications in bone marrow transplant recipients include infectious and noninfectious pneumonitis, GVHD (only for ALBMT recipients), obstructive pulmonary disease, and pulmonary vascular abnormalities. 1 Only a few studies have compared the incidence, the causes, and the mortality of pulmonary infectious complications following allogeneic and autologous bone marrow transplantation (BMT) for hematologic malignancies; 2 ·3 in this retrospective study, we report our experience with this concern.

ments were given when polymorphonuclear ~"unt was <500 nun'. Viral prophylaxis (oral aeydovir. 200 mg every 8 h) was given to ALBI\IT reeipients starting in July 1983; treatment with acyclovir was initiated 7 days before BMT infusion and was dis~'mtinued after 1 year. Beginning in Mard1 1989, ABMT patients also were given prophylaetil' oral acyclovir (200 mg every 8 h); treatment was started 7 days before BMT infusion and was discontinued 6 months aftt'r BMT. Both ALBMT and ABMT patients were given trinwtlwprim (160 mg) and sulfamethoxazole (800 mg) twice a day for 3 t-'lnsecutive days a week as prophylaxis of Pnerwwcysn~ carinii pneumonia; treatment was started when polymorphonuclear L~nmt was >500 mm 3 and was discontinued 12 months after hone marrow infusion. Benzathine, 1.2 million I U t'very 21 days, was administered as prophylaxis of pneumoL'(K'Cal pneumonia beginning after 1 year from ALBMT and was dis~'mtinued at the end of tht' second yt"ar after transplantation. Patients who underwent ALBMT were generally treated with busulfan (Bu) plus cyclophosphamide (Cy), or with Cy plus total body irradiation (TBI). The GVIID prophylaxis t'lnsisted of methotrexate and cydosporine, in combination or alone. Total body irradiation was given at 7.5 cGy/min from dual opposing '"Co source. The dose-fractionation of 200 rad twice a day fc>r 3 ~'mse~·utive days was generally given. The conditioning regimen administt'red to ABMT redpients has heen described in detail elsewllt're.' Lung biopsy sped mens and brondwalvt'olar lavages (BALs) were cultured for baeteria, fungi, mymhaeteria. and viruses by standard technic1ues. Lung biopsy spedmens were examined histologically with Gram-Veigert, hematoxylin-eosin, periodic add-Sehiff, Gomori mt'lhenamine silver, and add-fast stains.

~logeneic

METHODS

lbtients Charts of 130 L'msecutive patients who were submitted to ALBMT at the Department of llematoloh'Y of the University La Sapienza of Rome between July 1983 and April 1990 and charts of 290 mnsecutive patients who were submitted to ABI\IT between January 1985 and April 1990 at the same department were retrospectively evaluated. Both ALBMT and ABMT patients were given hacterial prophylaxis with oral quinolones (norHoxacin or ciproHoxacin, 400 mg and 500 mg, twice daily, respectively) and fungal prophylaxis (oral amphotericin B (2,000 m)!/d) from January 1983 to December 1989, and oral amphothericin B (same dosage) or oral Huconazolt' (150 m)!/d) from January 1990 onwards; both thest' prophylactic treat*From the Sezione Ematologia, Dipartimento di Biopatologia Umana, Universita La Sapienza, Rome, Italy. Manuscript received May 18, 1992; revision aceepted January 15, 1993. Reprint rr?quests: Dr. Martino, f:,UJtologia, Dip Histopatologia Umana, UniveT'sita ta Sapien::tl, Via B£•nevento 6, Rome, Italy 00161

ABMT=autologous bone marrow transplantation; ALBMT= allogeneic bone marrow transplantation; BU =busulfan; CMV =cytomegalovirus; Cy =cyclophosphamide; GVHD = graft-vs-host disease; IP =interstitial pneumonitis; TBI =total body irradiation

Classification of Pneumonia.~ Interstitial pneumonitis (IP) was defined as follows: evidenet• of hypoxemia (arterial Po, <60 mm llg at rcH>m air), respiratory alkalosis (arterial Pco, <30 mm Hg), and nonlobar pulmonary infiltratt' demonstrated radiographieally in the absence of ~·mg.. stive heart f>1ilure ;' inft'ctious causes were represented hy vi rust's, fimgi, and parasites and Wt'rt' dt'leeted from the lungs of patit"nts with IP either by BAL and/or lung biopsy ari(Vor at autopsy. Cytomegalo,·irus (CMV) IP was diagnosed by growth of the virus from lung tissut' or from BAL and idt'ntification of characteristic inclusions in lung tissue or, as from 1989, by the presence of CI\IV nucleic add sequences or by detedion of CMV antigens. Pneumocystis curinii IP was diagnosed when P carinii cysts were identified by mt•tllt'CHEST I 104 I 2 I AUGUST. 1993

371

Table 1- Patient Characteristics* ALBMT (n = 130)

ABMT (n = 290)

Without Pneumonia (n = 97)

With Pneumonia (n = 33)

Without Pneumonia (n = 278)

With Pneumonia (n = 12)

27.5

33 (9-48) 20/13

24 (1-55) 1781100

27 (10-55) 814

31 104 10 38 47

3 6 0

2 3

0 0

19 24

0 2 4

Median age, yr (range) Male/female Underlying disease ANLLCR ANLLRel ALLCR ALL Rei CML chronic phase CML accelerated fase CML blastic crisis Multiple myeloma Aplastic anemia Myelofibrosis Hodgkin's lymphoma Non-Hodgkin's lymphoma BMT conditioning regimen Bu/Cy Cy/TBI Cy/TBl/ARA-C Cy Etoposide/TBI Bu/Cy/ARA-C BACV CVB Bu/melphalan Other chemotherapy

(1-53)

55/42

1 34 15 35 7 3

6 0 4 15 4 1

0

1 0

27

4

54

45

17 9 1

12

10 12 2

2

0

5

99 18

0 0 2

2

93

*ANLL=acute nonlymphoid leukemia; ALL=acute lymphoid leukemia; CR=complete remission; Rel=relapse; CML=chronic myeloid leukemia; Bu =busulfan; Cy =cyclophosphamide; ARA-C = arabinosyl-cytosina; BAVC = BCNU + arabinosyl-cytosina + etoposide + AMSA; CVB=BCNU, etoposide, cyclophosphamide; TBI=total body irradiation; ALBMT=allogeneic bone marrow transplantation; ABMT =autologous bone marrow transplantation. namine-silver staining or by indirect immunoHuorescence with monoclonal antibodies in lung tissue or in BAL. Idiopathic IP was diagnosed whe n examination of lung tissue showed predominantly interstitial inHammation without histologic and microbiologic evidence of bacteria, viruses, fungi, and protozoa. Noninterstitial pneumonia (non-IP) was defined as a clinical syndrome characterized by either diffuse or localized pneumonia, as demonstrated at chest radiography. Bacterial or fungal non-IP was diagnosed whenever bacteria or fungi were isolated from blood cultures, BAL, or from sputum . Noninterstitial pneumonia was (.~ltlsidered of unknown origin if BAL and/or lung tissue were not obtained . Regarding ALBMT patients, cause of pneumonias was established by BALin 14 cases of 1P and in 2 cases of non-IP, by pulmonary biopsy specimen in 1 case of IP, and at autopsy in 3 cases of IP and in 5 cases of non-IP. Regarding ABMT recipients, cause of pneumonias was established by BAL in one case of IP and in two cases of non-IP. Pneumonias (both IP and non-IP) have been further characterized with regard to the onset; (."Onsidering time from BMT, they were categorized as early-onset (I to 30 days from BMT), middle-onset (31 to 100 days), and late-onset(> 100 days from BMT) pneumonias. Comparison of groups was accomplished by means of x• test. RESULTS

Characteristics of all patients submitted to BMT are described in Table 1. At the time this article was 372

written, 58/130 (44 percent) ALBMT and 103/290 ABMT (35.5 percent) patients were alive; the median follow-up of surviving ALBMT and ABMT patients was 1,610 days and 1,460 days, respectively. The occurrence of pneumonia increased with age following only ALBMT, as shown in Table 2. The incidence of IP in patients receiving Bu and Cy was equivalent to the incidence of IP in those given Cy and TBI, both in ALBMT and ABMT recipients (Table 3). The overall incidence of pneumonia in ALBMT recipients was Table 2-0ccurrence of Pneumonia by Age of Patients* No. of Patients With Pneumonia(%) Age, yr 0-9 10-19 20-29 30-39 40-49 50-60

Total

ALBMT l/13 4/23 7/27 13141 8125 0/1 331130

(7.6) (17.3) (25.9) (31.7) (32)

ABMT l/41 1174 5159 2/61 2/41 l/14 12/290

(2.4) (1.3) (8.4) (3.2) (4.8) (7.1)

*ALBMT =allogeneic bone marrow transplantation; ABMT = autologous bone marrow transplantation. Pneumonia in Bone Marrow Recipients (Gentile et al)

Table 3-Risk of Interstitial Pneumonitis (lP)

Tabk 5-Incidence of Pneumonia in 290 Autologous Bone Marrow Transplant Recipients With Regards to Onset*

Among lbtients Unckrgoing BMT According to

Preparative Regimen*

E (1-30)

Preparative Regimen Type of Transplant

Bu+Cy TotaiiP

CY+TBI TotallP

Allogeneic Autologous p value

1131 3/58 0 .56

6/62 0/13 0.30

p Value 0.25 0.5

*Ten of 19 cases of IP (14 ALBMT patients and 5 ABMT patients) are described in this table; the remaining 9 patients with IP were submitted to other preparative regimens. BMT= bone marrow transplantation; ALBMT=allogeneic BMT; ABMT=autologous BMT; Bu =busulfan; Cy =cyclophosphamide; TBI =total body irradiation.

25.3 percent (33 of 130 patients) (Table 4), while it was 4.1 percent (12 of 290 patients) in ABMT patients (p<0.0001) (Table 5). Patients with lymphoma submitted to ABMT were not at greater risk than those transplanted for acute leukemia (2/45 patients with lymphoma had pneumonia vs 10/192 patients with leukemia; p = 0.59). Regarding ALBMT patients, no patient with lymphoma was submitted to transplantation, whereas 11162 patients (17.7 percent) with acute leukemia developed pneumonia. Regarding IP, it occurred in 10.7 percent of all ALBMT patients (14 IPs of 130 patients), and it represented 42 percent of all pneumonias in ALBMT patients (14/33); conversely, IP occurred only in 5 instances in 290 ABMT recipients (1.7 percent). As shown in Table 4, most pneumonias in ALBMT (31 of 33) recipients occurred in the middle and late period from BMT, whereas in ABMT recipients, most pneumonias (10 of 12) occurred in the early and in the late period . The median onset of IP and non-IP after ALBMT was 70 days (range, 45 to 730 days) and 265 days (range, 8 to 1,250 days), respectively. The median onset of IP and nonIP after ABMT was 90 days (range, 56 to 180 days) and 26 days (range, 10 to 300 days), respectively. In 20 of 33 ALBMT patients (60.6 percent), it was possible to establish a definite diagnosis, CMV representing the major pathogen (13/20, 65 percent of all pneumonias in ALBMT) (Table 6). Pretreatment CMV serologic test was positive in 82 ALBMT recipients, negative in 20, and was not tested in 28 patients. In Table 4-lncidence of Pneumonia in 130 A&geneic Bone Marrow Transplant Recipients With Regards to Onset*

IP Non-IP Total(%)

E (1-30)

M (31-100)

L (>100)

li>tal (%)

2 2 (0.6)

12 5 17 (51)

2 12 14 (42)

14 (10.7) 19 (14.6) 33 (25.3)

*E =early period, days; M=middle period, days; L=late period, days. IP =interstitial pneumonitis.

IP Non-IP li>tal (%)

M (31-100)

L (>100)

li>tal

2 (17.5)

3 1 4 (33)

5 (1.7) 7 (2.4) I2 (4 . 1)

1 5 6 (50)

(%)

*E =early onset , days; M =middle onset, days; L =late mtSt•t , days. I P=interstitial pneumonitis.

contrast, no case of cytomegaloviral pneumonia was detected among patients receiving ABMT; CMV serologic testing was not performed in these patients. Fungi also represented a frequent cause of pneumonia, accounting for 18.1 percent of pneumonias (6 of 33) in ALBMT recipients, and for 16.6 percent (2 of 12) in ABMT recipients (Tables 6 and 7). Fungal pneumonias were caused by Aspergillus species in five ALBMT recipients and in two ABMT recipients. Candida species were considered the cause of pneumonia in one ALBMT recipient. Pneumocystis carinii was identified together with CMV in three instances of IP in ALBMT recipients. Most of the remaining pneumonias (13 of33 in ALBMT, and 9 of 12 in ABMT) were nonIPs of unknown origin (Tables 6 and 7). Idiopathic IP has been diagnosed in one ALBMT recipient. Eighteen of33 (54 percent) ALBMT patients developed acute GVHD (grade 1 to 4). Grade 1 to 3 GVHD was diagnosed in 9 of 13 patients with cytomegaloviral pneumonia; acute GVHD grade 2 to 3 was diagnosed in three of five patients with Aspergillus pneumonia. Twenty of 130 ALBMT patients (15.3 percent) and 6 of 290 ABMT patients (2.6 percent) died with or of pulmonary complications. Nine of 14 (64 percent) ALBMT recipients experiencing IP died . Six of the 9 (66.6 percent) patients with IP associated only with CMV died; 3 of3 patients with IP associated with CMV and another pathogen died. All four patients who survived their IP and CMV Table 6-Causes of Pneumonia in ALBMT Recipients and Correlation With Onset* E (l-30)

Viralt Bacterial:j:

L (>100)

ll

2 1 2 8 1 14

3 3

Fun~al§

Unknownll ldiopathit· li>tal

M (31-100)

()

()

2

17

1i1tal 13 I

6 12 1 33

*ALBMT = allo~eneic

bone marrow transplantation; E =early period, days; M =middle period, days; L =late period, days; CMV =

cytome~alovirus.

CMV. 3 CMV plus Pneumocystis carinii, 2 CMV plus species. :j:l\lycobact£'rium tuberculosis. §Five Asper~illus species. 1Candida species. IICiinically dia~nosed . tEi~ht

Asper~illus

CHEST I 104 I 2 I AUGUST. 1993

373

Table 7 -Causes of Pneumonia in ABMT Recipients and Correlation With Onset* E (1-30)

Viral Bacterialt Fungalt Unknown§ Idiopathic Total

M (31-100)

L (> 100)

Total

0 1

2

5 7

2

3

9

3

0 12

*ABMT =autologous

hone marrow transplantation; E=early period , days; M =middle period, days; L=late period, days. t Pseudomonas aeruginosa. tAspergillus species. §Clinically diagnosed .

had received ganciclovir alone or in combination with immunoglobulins, whereas only one of the nine patients who died had received ganciclovir. Eleven of 19 (57.8 percent) remaining ALBMT patients experiencing non-IP died . Two of five ABMT recipients with IP of unknown origin and four of seven patients with nonIF (Pseudomonas aeruginosa , one patient; Aspergillus species, two patients; and unknown origin, one patient) died. DISCUSSION

The overall incidence of pneumonias, and particularly of IP pneumonias, reported in this study in ALBMT and ABMT patients is lower than previously reported.3.5·6 The reasons for this variability may be related to differing definitions for interstitial pneumonia,a differing diagnostic criteria, and , most importantly, the relatively small number of patients studied at most centers. As far as risk factors are concerned, no difference was found either for preparative regimens or for underlying diseases (Table 1). As previously reported ,5 ·7 the incidence of pneumonias did increase with age in ALBMT patients, but not in our ABMT patients (Table 2). At the time the article was written, follow-up of surviving patients was 1,610 days for ALBMT (58/130 patients) and 1,460 days for ABMT (103/290); although there is a difference of 5 months in follow-up between the two groups, since most pneumonias occurred within the first 300 days from BMT (Tables 4 and 5), this difference seems not to correlate with the difference in incidence of pneumonias. Since BAL or pulmonary biopsy was performed in 20 of 33 ALBMT recipients, but in only 3 of 11 ABMT patients, the causes of pneumonia in our groups of patients cannot be correctly compared . Consequently, the spectrum of causes of pneumonias also appears not comparable in our two groups ofBMT patients; no CMV IP was documented following ABMT, whereas 13 episodes of CMV IP were documented after ALBMT. Fungal pneumonias occurred during the 374

middle and the late period following BMT, and, as previously reported, 9 most frequently occurred in patients who remained profoundly and persistently neutropenic and in whom BMT engraftment actually proved unsuccessful. The poor prognosis of invasive pulmonary aspergillosis is well known; 1o- 12 in the present study, all five patients with Aspergillus pneumonia died . Up to 30 to 40 percent of pneumonias occurring in ALBMT patients are reported to be idiopathic IP.S.S In our study, since pulmonary biopsies or autopsies were performed only in four ALBMT recipients with IP, we have observed one single case of idiopathic IP. Most of the pneumonias that occurred in both our groups of BMT recipients have been defined as pneumonias of unknown origin; however, since most patients with pneumonia received early empiric antimicrobial therapy with clinical cure , it could be hypothesized that our cases of non-IP pneumonia of unknown origin actually included many cases of nonidentified bacterial pneumonias. The types of pneumonia in our ALBMT patients differed according to the posttransplant interval: in fact, as shown in Table 4, most viral (Cytomegalovirus) pneumonias occurred during the middle period following ALBMT and were frequently related to GVHD , whereas most non-IPs occurred during the late period; these findings parallel those previously reported by other authors.6 The mortality related with pneumonia is reported as still high (20 to 30 percent) after allogeneic and autologous BMT.3 · 13 In our institution, the overall mortality, due to or associated with pneumonia after ALBMT, was comparable to data previously reported.6 In particular, in our study, the mortality of patients with CMV-related IP still has proved high (66 percent); however, it seems interesting to mention that all four patients who survived their IP had received therapy with ganciclovir, alone or in combination with immunoglobulins, 14 whereas only one of the nine patients who died had received this antiviral compound. Furthermore, recent studies 15 •16 have shown a 60 percent survival rate in BMT recipients treated for CMV pneumonia with ganciclovir and intravenous immunoglobulins. Previous studies3 •7 have shown that ALBMT patients transplanted for aplastic anemia were at lower risk for idiopathic IP than those transplanted for acute leukemia; in our study, cases of aplastic anemia (total= 2) were too few to make any comparison of risks. As far as ABMT patients are concerned, the incidence and mortality of IP has proved lower than previously reported;3 however, biases regarding diagnosis (unavailability of pulmonary biopsy specimens) do not allow us to draw pertinent conclusions in these regards. Pneumonia in Bone Marrow Recipients (Gentile et al)

As previously reported, 8 one of the most important risk factors for IP ov~rall, and particularly for CMV IP, is represented by acute GVHD. Graft-vs-host disease and its treatment can activate latent CMV infection in mice. 17 Activation of CMV can affect the recovery of the immunologic system; 18 • 19 indeed, in our study, all cas~s of fatal IP occurred in patients who developed severe GVHD (grade 3 or 4). In conclusion, the morbidity and mortality related to pneumonia after ALBMT and ABMT still seem to represent a very worrisome problem. Pneumonias in both groups of our patients often have been associated with a fatal outcome, and have indeed limited the ultimate rate of success of BMT. Even considering the diagnostic biases, in this large series of 420 BMT patients, we have been able to verify a wide difference between ALBMT and ABMT recipients regarding onset and types of pneumonias. Aggressive diagnostic maneuvers have been performed frequently in ALBMT patients due to the middle-period onset of pneumonias (mostly viral) that usually occur when immunologic defenses and/or bone marrow activity are already partially restored (ie, recovery of neutrophil and platelet count may allow invasive diagnostic procedures, like pulmonary biopsies). Conversely, early onset of pneumonias in our ABMT patients has usually coincided with the timing of profound immunodepression and bone marrow aplasia, thus making it difficult to perform invasive procedures. Further prospective studies should be aimed at increasing diagnostic proof in order to allow early and pertinent antimicrobial treatments and possibly positively influence the outcome. ACKNOWLEDGMENT: The authors are indebted to Ruggero Raccah, M.D., for his editorial assistance.

5

6

7

8

9

10 11

12

13

14

15

16

REFERENCES Krowke MJ, Rosenow EC, Hoagland HC. Pulmonary complications of bone marrow transplantation. Chest 1985; 87:237-45 2 Wingard JR, Chen DH, Burns WH, Fuller DJ, Braine HG, Yeager AM, et al. Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation. Blood 1988; 71:143238 3 Wingard JR, Sostrin MB, Vriesendorp HM, Mellits ED, Santos JW. Fuller D J, et al. Interstitial pneumonitis following autologous bone marrow transplantation. Transplantation 1988; 46:61-5 4 Meloni G, De Fabritiis P, Petti MC, Mandelli F. BAVC regimen

17

18

19

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