Pulmonary infections in cancer and bone marrow transplant patients

Pulmonary Infections in Cancer and Bone Marrow Transplant Patients Judith M. Aronchick

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ULMONARY INFECTION in the cancer patient is a significant cause of morbidity and mortality. With increasing numbers of cancer and bone marrow transplant patients, the incidence of serious pulmonary infection also increases. The causes of infection in this population are multifactorial. The risk of infection is related to immune defects caused both by the tumor and chemotherapy, as well as nosocomial exposures. Chemotherapy produces profound neutropenia, as well as significant damage to mucosal surfaces, both of which increase the risk of infection. HOST-DEFENSE MECHANISMS

The three components of the host immune system include granulocytes, B-lymphocytes, and Tlymphocytes. Defects in any of these will result in an increased risk of infection. The organisms most likely to cause infection will depend on which arm of the immune system is defective (Table 1). In addition, protection from pulmonary infection also requires normal function of local factors, including the mucociliary clearance system as well as normal function of bronchial surface fluids and epithelial lining cells. These local factors enable the host to entrap and clear organisms before infection can occur.

Neutropenia Granulocytes are required for phagocytosis. Neutropenia, which is seen primarily after chemotherapy, predisposes the patient to infection by extraceltular or pyogenic bacteria and fungi. Organisms most commonly producing pneumonia in the setting of neutropenia are Streptococcus pneumoniae,

Viridans streptococci, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella, Escherichia coli, Aspergillus, Fusarium, Mucor, Candida, and Blastoschizomyces. 1 From the Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, PA. Address reprint requests to Judith M. Aronchick, MD, Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia, PA 19104. Copyright 9 2000 by W.B. Saunders Company 0037-198)(/00/3502 -0005510. 00/0 doi: l O.l O53/ro.2000.6152 140

In cancer patients, neutropenia is usually caused by cytotoxic chemotherapy. Neutropenia is also seen in hematopoietic malignancies, especially acute leukemia, when the bone marrow is replaced by malignant cells and is unable to produce normal neutrophils. As the granulocyte count decreases, the risk of infection increases. Neutropenia is present when the granulocyte count is less than 1,000 granulocytes per mm 3. The risk increases as the count falls below 500 per mm 3. and is greatest when the granulocyte count is less than 100 per m m 3.2,3 The rate of decline of granulocytes, as well as the duration of neutropenia, influences the risk of infection. Patients with rapidly falling neutrophil counts are at greater risk of infection than patients with slowly falling counts. 4 Patients are most susceptible to bacterial infections early in the neutropenic period. As neutropenia persists, opportunistic fungal infections, especially aspergillus, become more common.

Defects in Humoral and Cellular Immunity Humorat immunity is mediated by B-lymphocytes, which differentiate into antibody-secreting plasma cells when stimulated by an antigen. Deficiencies in B-cell function are most commonly seen in patients with lymphoproliferative disorders, following chemotherapy, and in bone marrow transplant patients. Defects in humoral immunity are most often associated with infections by encapsulated organisms, such as Streptococcus pneumoniae and gram-negative organisms such as Hemophilus influenzae, Neisseria meningitidis, and

Pseudamonas aeruginosa. 1 Cellular immunity is mediated by T lymphocytes, which undergo lymphoblastic transformation when stimulated by an antigen. Cellular immunity is affected in patients with lymphoproliferative disorders, patients receiving chemotherapy, bone marrow transplant patients, solid organ transplant patients, and patients on steroids. Patients with T-cell dysfunction are susceptible to more unusual pathogens, including viruses (cytomegalovirus, vari-

celia virus, herpes zoster virus, Epstein-Barr virus), protozoa (Pneumocystis carinii, Toxoplasma gondii), fungi (aspergillus, Cryptococcus neoforroans, Histoplasma capsulatum, Coccidioides immiSeminars in Roentgenology, Vol XXXV, No 2 (April), 2000: pp 140-151

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Table 1. Immunological Deficiencies and Associated Infections

Causes Neutropenia

Chemotherapy BMT Myeloproliferative disorders

T-Lymphocyte dysfunction

Chemotherapy BMT Lymphoproliferative disorders Solid organ transplant Steroids

B-Lymphocyte dysfunction

Chemotherapy BMT Lymphoproliferative disorders

AssociatedInfections Bacterial Gram-negative: Pseudamonas, E. coli, Klebsiella, Enterobacter Gram-positive: S. pneumoniae, S. aureus, Viridans streptococci Fungal Aspergillus, Candida, Mucor, Fusarium, Blastoschizomyces Fungal Aspergillus, Cryptococcus, Histoplasma, Coccidioides Viral CMV, HSV, RSV, VZV Protozoan P. carinii, Toxoplasma Bacterial Legionella, Nocardia, Mycobacteria Helminths Strongyloides Bacterial S. pneumoniae, H. influenzae, other gram-negative

Adapted and reprinted with permission?

tis), bacteria (Legionella pneumophila, Nocardia asteroides, Listeria monocytogenes, salmonella, and mycobacteria) and helminthic infections such as Strongyloides. 1 THE BONE MARROW TRANSPLANT PATIENT

Bone marrow transplantation was first introduced in the late 1960s and is used with increasing frequency in the treatment of patients with lymphoma, leukemia, anemias, multiple myeloma, congenital immunological defects, and solid tumors. Patients undergoing bone marrow transplantation first receive high-dose chemotherapy and sometimes additional total body radiation designed to eradicate the malignant cells from the endogenous bone marrow and to ablate the patient's immune system. Following the conditioning phase, the patient receives an intravenous infusion of hematopoietic progenitor cells to repopulate the marrow and establish marrow function. The patient's own bone marrow (autologous transplant) or marrow from a human leukocyte antigen (HLA)-matched donor (allogeneic transplant) may be used. Profound immune impairment is present following bone marrow transplantation. Severe neutropenia lasts for 2 to 3 weeks after the transplant, at which time marrow engraftment takes place. Although the neutrophil counts increase following engraftment, normal immune function does not return immedi-

ately and significant impairment persists for 4 to 5 months. Full recovery of humoral and cellular immunity occurs gradually over the course of 1 year following bone marrow transplantation.

Pre-Engrafiment Severe neutropenia is the hallmark of the first 3 weeks following bone marrow transplant and puts the patient at significant risk for bacterial and fungal infections. Bacteremias are common during this period, but empiric use of broad-spectrum antibiotics for febrile episodes has resulted in a marked reduction of bacterial pneumonias. Most pulmonary infections during this period are caused by opportunistic fungi, with aspergillus as the most common fungal pathogen. 5 Fusarium, Cryptococcus, Candida, and Mucor are less common causes of fungal pulmonary infection in the pre-engraftment period. Other significant pulmonary complications during the first 3 weeks following bone marrow transplant include diffuse alveolar hemorrhage, pulmonary edema, and drug toxicity.

Post-Engraftment (31 to 100 days following bone marrow transplant) As marrow engraftment progresses 2 to 3 weeks after transplant, neutrophil counts begin to rise. However, significant defects in cellular and humoral immunity persist for approximately 100 days

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following transplant. After the first month following transplant, the patient is most susceptible to viral and protozoan pathogens. Cytomegalovirus (CMV) is the most common cause of pulmonary infection during this period. 6.7 Patients are also highly susceptible to infection with pneumocystis. However, routine prophylaxis for pneumocystis in these patients has dramatically decreased the incidence of pneumocystis pneumonia. Following bone marrow transplant, a number of defects occur in the host and immune system. Initially after transplant, donor lymphocytes from the transplanted bone marrow may convey passive T-cell immunity, which is partially effective for approximately 2 months. Native host lymphocytes that have survived radiation therapy and chemotherapy may also provide limited cellular immunity during this period. The period of greatest immune deficiency following bone marrow transplant occurs after the loss of native immunity and passive donor immunity, and before the development of immune function from the transplanted marrow. This occurs from day 50 to day 100 and is the period of greatest risk for infection. 8 In patients with graft-versus-host disease (GVHD), recovery of immune function is further delayed. In addition, GVHD damages epithelial cells in the skin, liver, and mucous membranes, further increasing the risk of infection. CMV is the most common pathogen during this period, s

Late Post-Transplantation Period (more than 100 days) Recovery of cellular and humoral immunity occurs gradually over the course of a year in bone marrow transplant patients. Pulmonary infection in the late post-transplantation period is most often seen in patients who develop chronic GVHD. Chronic GVHD occurs in 35 to 50 percent of allogeneic transplant patients j,9 and develops approximately 3 months after the transplant. Chronic GVHD produces intrinsic immunodeficiency. These patients are treated with increasing immunosuppressive therapy, which further compromises their immunity. Encapsulated bacteria and Pneumocystis are the major causes of pulmonary infection during this period, l Although infection may occur, it is not common in the late post-transplant period. Major pulmonary complications during this period are usually nonin-

JUDITH M. ARONCHICK fective. These include bronchiolitis obliterans, bron-

chiolitis obliterans with organizing pneumonia, and chronic GVHD. BACTERIAL PNEUMONIAS

During the early stages of immune compromise, bacteria are the most common source of lung infection in cancer patients and bone marrow transplant patients. Predisposing factors include bacteremia, disruption of mucosal barriers, defective ciliary function in the tracheobronchial tree, aspiration, and endotracheal intubation. Because of the early use of empiric broad spectrum antibiotics in febrile neutropenic patients, the incidence of bacterial pneumonia has decreased. The incidence of bacterial pneumonia in the BMT patient is approximately 12% to 15% m,~ in the first 100 days post-transplant, and is more common in allogeneic than in autologous transplant patients. Although healthy patients develop communityacquired pneumonia with both gram-positive and gram-negative organisms, immunocompromised patients are at risk for developing gram-negative pneumonias, The flora of the oropharynx changes in patients who are ill or hospitalized. These patients become colonized with more virulent gramnegative bacilli, and therefore are more likely to develop virulent gram-negative pneumonias. Among gram-negative organisms, Pseudomonas is most commonly isolated as the cause of pneumonia in neutropenic patients. 1 There are increasing reports of gram positive pneumonias 12,13 in immunocompromised patients, probably related to the widespread use of indwelling central venous catheters. S. pneumoniae has become more common in neutropenic patients and as a late infection in BMT patients with chronic GVHD. Of growing concern is the rise of antibioticresistant strains of S. pneumoniae. Streptococcus viridans has been seen with increasing frequency in leukemia patients with severe oropharyngeal mucositis following high-dose ARA-C. Bacteremia followed by pneumonia and fatal ARDS has been described in these patients.~4 S. aureus pneumonia may also occur in neutropenic patients. The most common radiological pattern of bacterial pneumonia in the normal host or the immunocompromised host is a focal area of dense alveolar consolidation. The infiltrate may be lobar or segmental (Fig 1). In the immunocompromised patient,

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culture, frequently a definitive diagnosis is not obtained and the patients are treated empirically with broad spectrum antibiotics. Nocardia asteroides is an opportunistic bacterium that occurs in patients with defective cellular immunity. Neutropenia is usually not present, but a history of steroid therapy commonly precedes nocardia infection. ~6 The most common radiographic pattern seen with nocardia pulmonary infection is a slowly progressive nodular infiltrate (Fig 2). The nodules may be single or multiple and cavitation may occur. The masslike infiltrate may extend to the pleura and cause pleural effusion. 15 Pleural effusions occur in up to 50% of patients with nocardia.17 They may be unilateral or bilateral. Nocardia may also involve the skin, brain, and meninges. Although the diagnosis is sometimes made by sputum smear or culture, invasive procedures are usually required. FUNGAL PNEUMONIA

Fig 1. Right middle lobe pneumon,a is shown in a 36-yearold man with leukemia, new fever, and productive cough. Pneumonia cleared with antibiotics, presumed to be bacterial.

cavitation is common and may be solitary or may be multiple. Bacterial pneumonia in these patients may produce multilobar patchy areas of consolidation. Pleural effusions may be present and are typically small. Empyemas are unusual. ~-~Although a diagnosis may be made from sputum or blood

Pulmonary fungal infections are a major cause of death in immunocompromised patients. Opportunistic infections with aspergillus, candida, cryptococcus, and mucor occur in neutropenic patients. Reactivation of indolent infection with organisms, such as Histoplasma and Coccidioides, may be seen in patients with abnormal cellular immunity. 18 Aspergillus is the most common cause of fungal pneumonia in the neutropenic cancer patient and in bone marrow transplant patients. Aspergillus infection has been reported in up to 20% of bone marrow transplant patients, j9 Prolonged neutropenia, steroid therapy, broad-spectrum antibiotics, GVHD, and transplantation of T-cell depleted marrow all predispose the patient to aspergillus infection. Mortality is reported to be up to 60% in neutropenic patients and up to 90% in bone marrow transplant patients. 9,2~ Airborne exposure is the primary route of infection, and the organism spreads from membranous and respiratory bronchioles to adjacent alveoli. At this stage, the chest radiograph will show an ill-defined area of opacification. Aspergillus pulmonary infection is characterized by vascular invasion, and a necrotizing pneumonia with hemorrhagic infarction develops as the infection progresses. The subtle focus of ill-defined opacity becomes a well-defined nodular infiltrate (Fig 3). The infection most often produces multiple patchy nodules, often abutting the pleural surfaces.

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Fig 2. A 5g-year-old man is shown 8 months after allogeneic bone marrow transplant with GVHD and new fever, (A) Chest radiograph shows ill-defined nodular opacities in left upper lobe and left lower lobe with left pleural effusion, (B and C) CT scan 3 weeks later shows multifocal nodular infiltrates and right pleural effusion. Nocardia recovered on thoracoscopic biopsy.

On CT, the characteristic appearance of aspergillus is a parenchymal nodule of dense consolidation surrounded by a halo of ground glass attenuation (Fig 3). 21 This corresponds to the lung pathology, which classically shows central fungal infection in the lung parenchyma surrounded by hemorrhagic infarction due to invasion of adjacent vessels. Sometimes, infarction will cause a characteristic wedge-shaped opacity. As the patient recovers from neutropenia, the fungal nodules will frequently show cavitation, producing the classic air crescent sign seen on chest radiograph and also on CT (Figs 4 and 5). This radiographic finding signals a rising neutrophil count in the infected patient. 22,23 The diagnosis of aspergillus frequently requires percutaneous aspiration or thoracoscopic lung biopsy. Aspergillus is often found in sputum as a contaminant, and the diagnosis requires a positive patho-

logical sample. However, in the bone marrow transplant population, the detection of aspergillus in the sputum has a 95% positive predictive value for true infection. 24 Treatment is with amphotericin B. Other fungal pneumonias are much less common in cancer and bone marrow transplant patients. Mucor occurs occasionally in patients with neutropenia, lymphoproliferative disease, and prior antibiotic therapy. Mucor is also an angioinvasive fungus and the radiographic appearance is similar to that of aspergillus. Biopsy is usually required for diagnosis. Amphotericin B is used for treatment. Although candida infection is common in bone marrow transplant patients, primary pulmonary infection with candida is uncommon. Lung involvement occurs during disseminated fungemia with candida. The chest radiograph appearance is nonspecific and may show air space consolidation with a

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A

Fig 3. A 47-year-old man with refractory acute myelogenous leukemia, fever, and neutropenia is shown. (A) Baseline chest radiograph. (B) Three weeks later, ill-defined opacity right upper lobe. (C) Two days after B, dense nodular masslike opacity right upper lobe. (D) CT shows dense right upper lobe consolidation with surrounding halo of ground glass opacity. Aspergillus was obtained on transthoracic needle biopsy.

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Fig 4. A 36-year-old woman with acute leukemia, fever, and neutropenia is shown. (A) Baseline chest radiograph. (B) Five days later, chest radiograph shows nodular infiltrate in left upper lobe. Aspergillus is present in bronchoscopic lavage fluid.

segmental, lobar, or diffuse distribution. 7 Diagnosis is usually made by biopsy. Cryptococcus in the immunocompromised host usually presents as a disseminated infection, with skin lesions and central nervous system involvement being most common. Neurological symptoms are often the first manifestation of cryptococcal infection. Cryptococcal lung infection, which is much less common than aspergillus pneumonia, appears radiographically as single or multiple nodules, with or without cavitation.15 Lobar or segmental consolidation may occur as well. The diagnosis is difficult to make by sputum culture and is usually

made by serum cryptococcal antigen titers or by cerebrospinal fluid culture following lumbar puncture. Therapy is with amphotericin B and 5-flucytosine. VIRAL PNEUMONIA

CMV is the most common cause of viral pneumonia in the bone marrow transplant patient. 6,7 It is most often seen approximately 50 to 60 days after transplant 25 and may develop any time during the post-engraftment phase (50 to 100 days after transplant). Ten percent to 40% of bone marrow transplant patients will develop CMV pneumonia, 5 with

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C Fig 4. (cont'd). (C) Three weeks later, the chest radiograph shows a classic air-crescent sign in left upper lobe cavity with intracavitary debris. The patient's neutrophil count had rebounded to normal at the time of this chest radiograph.

a mortality rate of 85%. 8 Of bone marrow transplant patients who are seropositive for CMV, 70% will develop infection from reactivation of latent endogenous virus. In patients who are seronegative for CMV, approximately 36% will develop CMV infection from infusion of seropositive marrow or blood products from seropositive donors. 5 The risk factors for CMV pneumonia include seropositive recipients, seronegative recipients receiving marrow from seropositive donors, older age, total body

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irradiation, severe GVHD, frequent transfusions, and use of antirejection drugs causing T-cell depletion. Radiographic findings in CMV pneumonia include diffuse interstitial opacities, which are usually reticulonodular or nodular, or diffuse air space disease (Fig 6). The characteristic CT findings are disseminated small nodules (1 to 5 mm) with associated ground glass opacities. 26 The diagnosis of CMV pneumonia is made by bronchoscopy; on histology the bronchoalveolar lavage (BAL) specimens show pulmonary macrophages with characteristic inclusion bodies. Early diagnosis and treatment with ganciclovir and high-dose immunoglobulin has resulted in improved survival. 27 Because of the high mortality of CMV pneumonia in bone marrow transplant patients, anti-CMV prophylaxis is becoming more common in BMT patients. Herpes simplex virus (HSV) is a less common cause of viral pneumonia, affecting less than 5% of BMT patients, t2 Infection with HSV generally occurs during profound neutropenia in the first 3 weeks after transplantation and is associated with severe damage to mucous membranes. Infection starts in the mouth and throat and may spread to the respiratory tract. Lung involvement may produce focal or multifocal opacities on chest radiograph or may produce a diffuse interstitial patternY A recent report has shown an association of human herpes virus-6 (HHV6) with idiopathic interstitial pneumonia in BMT patients. 28 The incidence of this infection is not clearly defined. Infection with herpes zoster and varicella pneumonia may also occur (Fig 7). Other less common causes of viral infection in BMT patients include respiratory syncytial virus and parainfluenza virus (Fig 8). These infections typically begin in the upper respiratory tract and may spread to the lungs. The development of pneumonia carries a mortality of up to 50%. ~9 Chest radiograph findings are nonspecific and may include focal opacities or diffuse parenchymal involvement. 30

PNEUMOCYSTIS CARINII

Pneumocystis carinii is an important cause of pneumonia in patients with impaired cellular immunity. However, the routine use of PCP prophylaxis with trimethoprim sulfamethoxazole in BMT patients has greatly reduced the incidence of PCP to

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Fig 5. A 39-year-old woman with leukemia, treated with chemotherapy, who presented with neutropenic fever is shown. (A) CT shows well-defined left upper lobe nodule. The patient was treated presumptively for aspergillus. (B) Twelve days later, CT shows air-crescent in left upper lobe nodule and a second nodule in right upper lobe. Follow-up studies showed complete resolution of invasive aspergillosis.

less than 10%. 5,31 BMT patients usually receive prophylaxis for 1 year after transplant. The onset of PCP in the BMT population is rapid, with development of a diffuse reticular pattern on the chest radiograph, which may progress to diffuse air space disease (Fig 9). The characteristic pattern on CT is diffuse ground glass attenuation. 32 Less commonly, CT will show scattered nodules and occasionally cavities will occur. The CT scan, especially HRCT, may show parenchymal abnormality, whereas the chest radiograph appears normal. 15 Diagnosis usually requires bronchoscopy with biopsy or BAL.

DIFFERENTIAL DIAGNOSIS

Although infection is a major cause of pulmonary disease in the bone marrow transplant patient, other complications are common as well. Pulmonary edema and diffuse alveolar hemorrhage occur relatively early after BMT. Idiopathic interstitial pneumonia is usually seen in the post-engraftment phase. Bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, and chronic GVHD are late post-transplant complications.

Pulmonary Edema Pulmonary edema is a common early complication following bone marrow transplant, occurring in the second or third week after transplant. 5

Fig 6. A 21-year-old immunocompromised woman with CMV pneumonia diagnosed by bronchoscopy. Chest radiograph shows diffuse interstitial infiltrate with patchy nodules.

Fig 7. A 37-year-old man with acute leukemia who presented with chicken pox and dyspnea is shown. Chest radiograph shows disseminated patchy nodules secondary to varicella pneumonia.

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tion combined with episodes of sepsis. The chest radiograph shows diffuse interstitial opacities progressing to diffuse air space disease frequently associated with vascular congestion, vascular redistribution, and pleural effusions.

Diffuse Ah,eolar Hemorrhage

Fig 8. A 44-year-old w o m a n w i t h multiple myeloma, treated w i t h chemotherapy and presenting with fever. Chest radiograph shows diffuse airspace disease secondary to parainfluenza viral pneumonia.

Pulmonary edema during this phase is frequently cardiogenic and is associated with infusion of large volumes of fluid needed to administer antibiotics, blood products, and parenteral nutrition. Underlying cardiac and renal dysfunction from prior chemotherapy also contribute to cardiogenic pulmonary edema. Noncardiogenic edema also occurs during this phase and is frequently secondary to lung injury from chemotherapy or total body irradia-

Diffuse alveolar hemorrhage has been reported in both autologous and allogeneic transplant patients but is more common after autologous bone marrow transplant, occurring in 21% of such patients. 33 The onset is 7 to 40 days post-transplant but is most common at approximately 12 days after transplant. Of interest, the patients usually present with cough, fever, and hypoxemia in the absence of hemoptysis. Chest radiograph shows alveolar infiltrates, which frequently progress to diffuse bilateral disease. On CT, bilateral areas of ground glass attenuation or consolidation are seen. 32 The diagnosis is made on bronchoscopy; BAL reveals blood with hemosiderin-laden macrophages. Hemorrhage occurs at the time of marrow engraftment and is thought to result from inflammation caused by the influx of neutrophils in the lungs. The prognosis is poor, with 50% to 80% mortality. 33

Idiopathic Pneumonia Syndrome Idiopathic pneumonia syndrome (IPS) is a diagnosis of exclusion and is defined as diffuse lung

Fig 9. A 47-year-old w o m a n 10 months after bone marrow transplant, who presented with cough and dyspnea is shown. (A) Chest radiograph shows diffuse airspace disease. Pneumocystis cariniiwas recovered in bronchoscopic lavage fluid. (B) Two days

later, the chest radiograph shows marked progression of diffuse airspace disease.

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injury that occurs after bone marrow transplant in the absence of an infectious agent. It is thought to be a manifestation of pulmonary toxicity related to pretreatment regimens. IPS occurs in approximately 12% of allogeneic bone marrow transplant patients 34 and is associated with GVHD as well as high doses of total body irradiation. 35 This complication is seen within the first 80 days after transplant and is most common 42 to 49 days after transplant. IPS may also occur within the first 2 weeks after BMT. Histology shows diffuse alveolar damage with an interstitial mononuclear infiltrate. The chest radiograph is nonspecific, frequently showing multilobar infiltrates. In patients who undergo bronchoscopy, BAL shows no evidence of infectious pathogens. In patients with IPS, the mortality approaches 70%. 5

Graft- Versus-Host Disease GVHD is an immune reaction resulting from donor T lymphocytes that recognize the recipient's tissue as foreign. Acute GVHD occurs in the first 100 days after allogeneic BMT, and affects 25% to 75% of BMT patients. Acute GVHD usually involves skin, liver, and GI tract, and rarely involves the lungs. 36,37 Chronic GVHD is a multiorgan disorder involving skin, eyes, lung, liver, and GI tract and is associated with immunodeficiency and opportunistic infection. Pulmonary involvement includes infection with encapsulated bacteria, aspergillus, PCP, and chronic aspiration. Noninfectious pulmonary complications of chronic GVHD include chronic bronchitis, progressive obstructive airway disease, bronchiolitis obliterans, and lymphoid interstitial pneumonia. Twenty percent to 45% of BMT patients alive at 6 months will develop chronic GVHD. In two thirds of these patients, chronic GVHD is preceded by acute GVHD. 9

Bronchiolitis Obliterans Bronchiolitis obliterans (BO) is a late complication following allogeneic bone marrow transplant with an incidence in the range of 2% to 13%. It rarely occurs after autologous bone marrow trans-

plant. BO is more likely to occur in patients with depressed immunoglobulin level following transplant and in patients with chronic GVHD. 36,38 BO usually develops at least 3 months after bone marrow transplant and is of uncertain origin. It has been suggested that BO may be the result of damage to small airways caused by GVHD or an autoimmune process involving the bronchial tree. 38 Pulmonary function tests show nonreversible airflow obstruction and abnormal diffusing capacity. Thin section CT demonstrates dilated bronchi, a mosaic pattern of attenuation and air trapping on expiratory scans. 32 Mortality is greater than 50%. 5

Bronchiolitis Obliterans With Organizing Pneumonia Bronchiolitis obliterans with organizing pneumonia (BOOP) is another late complication seen in bone marrow transplant patients. The presentation is similar to the presentation of BOOP in normal hosts and consists of cough, dyspnea, and lowgrade fever. The chest radiograph shows patchy multifocal areas of consolidation. CT findings are typically patchy consolidation frequently in a subpleural or peribronchial location, ground glass opacity, or well-defined nodules. The ground glass opacities and nodules are randomly distributed. 32 Treatment is with steroids and is usually effective. CONCLUSION

Cancer patients and bone marrow transplant patients suffer a variety of immunological abnormalities, which put them at risk for overwhelming opportunistic lung infections as well as the usual community acquired pneumonias. The morbidity and mortality from these infections can be quite high. The organisms most likely to cause pneumonia in the immunocompromised host depend on the precise immunological deficiency and the time course of the compromised immune state. Although the imaging findings may be nonspecific, often the chest radiograph and CT scan, in conjunction with an accurate clinical history, may allow the radiologist to provide a narrow differential diagnosis.

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