Special Feature
Noninfectious Lung Disease in the Immunocompromised Host
By Stephen W. Crawford, MD
Patients with compromised immune function risk a wide variety of lung insults. Patients in the intensive care unit (ICU) may be particularly at risk. Infections are the most common causes of both acute and chronic lung diseases, but many noninfectious conditions affect the lungs. The clinical presentations of these noninfectious conditions often mimic infections, and this causes diagnostic dilemmas. In the ICU the urgency to resolve these dilemmas is heightened. Causes of acute and chronic pulmonary injury among immunosuppressed patients include a multitude of drugs, radiation, and systemic infection or inflammation causing acute respiratory distress syndrome (ARDS) (see Table 1).1,2 Alveolar hemorrhage may complicate any of these conditions. In addition, vascular and airway lesions that are apparently immunologically mediated occur in transplant recipients.
| Table 1-Characteristics of Noninfectious Pulmonary Diseases in Immunocompromised Hosts | ||
| Etiology | Chest Radiograph | Associations |
| Leukemic infiltrates | Focal or multifocal | Leukemic blasts |
| Leukostasis | Diffuse | Leukemic blasts |
| Hemorrhage | Diffuse or focal | Thrombocytopenia |
| Uremia | ||
| Bleeding diatheses | ||
| Idiopathic pneumonia | Diffuse | ARDS |
| Drugs: | ||
| Alkylating agents | ||
| Bleomycin | ||
| Mitomycin C | ||
| BCNU/CCNU | ||
| Methotrexate | ||
| Cytosine arabinoside | ||
| Interleukin 2 | ||
| Cardiac edema | Diffuse, cardiomegaly,Pleural effusions | Drugs: Cyclophosphamide, Anthracyclines |
Further confusing the topic of noninfectious lung injury in immunosuppressed patients is the fact that diffuse pulmonary infiltrates due to cardiac pulmonary edema as a result of cardiotoxicity may have similar clinical presentations as noninfectious pneumonia (see Table 2). Many of the causes of noninfectious pulmonary disease result in similar radiographic and clinical presentations. However, the pathological patterns of the processes may vary widely. Few of the pathologies are pathognomonic and most are only suggestive of the etiology of the injury. Noninfectious pulmonary diseases among immunosuppressed patients most often present Table 1 as diffuse pulmonary infiltrates on chest radiograph. During treatment for leukemia more than half of all such presentations are due to noninfectious causes.3
| Table 2-Selected Causes of Radiographic Infiltrates in Immunocompromised Hosts | |||
| Diffuse | Focal | Multifocal | |
| Noninfectious | Idiopathic | ||
| Idiopathic pneumonia | |||
| ARDS | |||
| Alveolar hemorrhage | |||
| Edema | |||
| Heart failure | |||
| Volume excess | |||
| Capillary leak syndromes | |||
| ARDS | |||
| Acute GVHD | |||
| Leukemic infiltrate | Leukemic infiltrate | Leukemic infiltrate | |
| Fat emboli syndrome | |||
| Lymphoma | Lymphoma | ||
| Pulmonary embolus | Pulmonary emboli | ||
| BOOP | BOOP | ||
| Aspiration | |||
| Infectiou | Viral | Viral | |
| CMV | |||
| RSV | |||
| Parainfluenza | |||
| Influenza | |||
| Adenovirus | |||
| HSV | HSV | ||
| VZV | VZV | ||
| HHV-6 | |||
| Fungal | Fungal | Fungal | |
| Mycelial fungi | Mycelial fungi | Mycelial fungi | |
| Yeast | |||
| Pneumocystis carinii | |||
| Bronchopneumonia | Bronchopneumonia | ||
| Gram (+) bacteria | Gram (-) bacteria | ||
| Gram (-) bacteria | Gram (-) bacteria | ||
| Legionella species | Legionella species | ||
| Nocardia | Nocardia | ||
| Mycobacteria | Mycobacteria | ||
| Toxoplasmosis | |||
| Toxoplasmosis | Septic emboli | ||
| acute respiratory distress syndrome (ARDS); graft vs. host disease (GVHD); bronchioliterans with organizing pneumonia (BOOP); cytomegalovirus (CMV); respiratory syncytial virus (RSV); herpes simplex virus (HSV); varicella-zoster virus (VZV); human herpes virus 6 (HHV-6). | |||
Pulmonary complications in the immunosuppressed may either be acute or chronic in nature. Inciting causes may be associated with either or both presentations. The constellation of symptoms and signs accompanying these infiltrates may vary from minimal to profound respiratory failure. Unfortunately, the presentation is rarely of clinical use in pinpointing a specific cause. Confirmation of the diagnosis may not be as relevant as is the exclusion of opportunistic infection or cardiac pulmonary edema as causes of the process. With the possible exception of cardiac pulmonary edema, most causes of diffuse noninfectious pulmonary injury are associated with a poor prognosis. Specific treatments rarely have been proven to be effective.
Irradiation Lung Injury
Two types of radiation-induced lung injury—radiation pneumonia and radiation fibrosis—are observed among patients who have undergone thoracic irradiation for the treatment of lung, breast, or hematologic malignancies. Radiation-induced damage to normal lung parenchyma is the limiting factor in chest radiotherapy.
Ionizing radiation causes the localized release of large amounts of energy, sufficient to break a strong chemical bond. Macromolecules such as peptides, lipids, and DNA may be damaged by direct disruption, or indirectly through the interaction of the ionizing radiation with tissue water. During normal host cell repair not all DNA breaks are corrected, leaving the damaged cells susceptible to necrosis with their next division.
There is a threshold dose under which no injury is detectable, followed by a steep dose-response curve at higher radiation levels.4,5
Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a) and interleukin 1-alpha (IL-1a), and potent fibroblast mitogens, platelet-derived growth factor (PDGF) and b-FGF, are upregulated after lung irradiation and are thought to mediate the pathologic changes.5 A less common and unpredictable lung injury also has been described that involves a CD4+ lymphocytic alveolitis in both irradiated and nonirradiated lung, suggesting a hypersensitivity pneumonia-like reaction.5
Factors associated with the development of radiation-induced lung disease include the following:
• A large volume of lung irradiated (exceeding 10%)
• Daily dose fractions of radiation greater than 2.67 Gy13
• A high cumulative dose of radiation
• Concurrent chemotherapy with agents that are known sensitizers to radiotherapy, such as: Dactinomycin Bleomycin
Cyclophosphamide Vincristine Recombinant interferon-alpha
• Prior thoracic irradiation
• Volume loss due to lung collapse
• Younger age
• Steroid withdrawal during radiotherapy6,7,8
The pathologic and clinical changes in the lung after irradiation progress through stages.9 Initially, there is an asymptomatic phase, characterized by hyperemic, edematous mucosa with leukocytic infiltration within hours to days after radiation exposure. An exudative alveolitis follows. Next, in the "latent phase," thick secretions accumulate due to an increase in the number of goblet cells, and there is ciliary dysfunction. The third phase (acute exudative phase) develops 3-12 weeks after exposure and is referred to as radiation pneumonia. There is sloughing of endothelial and epithelial cells, narrowing of the microvasculature and capillary thrombosis, hyaline membrane formation, and hyperplasia with marked atypia in giant cells and type II pneumocytes may be seen. In the fourth phase (intermediate phase), there may be resolution of the alveolar exudate and hyaline membranes, or there may be collagen deposition by fibroblasts. A final phase consists of fibrosis. It may be apparent as early as six months after irradiation and can progress over years.
Symptoms of radiation pneumonia usually have an insidious onset and include nonproductive cough, dyspnea, fever, pleuritic or substernal chest pain, malaise, and weight loss. Rales or a pleural rub may be heard or, in some cases, auscultation can be normal. No commonly used laboratory test predicts the development of radiation pneumonia. A low-grade polymorphonuclear leukocytosis is often present. Chest roentgenograms may be normal in symptomatic subjects during the subacute phase. However, perivascular haziness may be present early and often progresses to patchy alveolar filling densities. A straightline effect, which conforms to the radiation port but not to anatomical lung units, is often seen and is virtually diagnostic of radiation-induced lung injury. A small pleural effusion may be present in about 10% of patients, but lymphadenopathy does not occur.
Chest computerized tomography (CT) is more sensitive than the chest roentgenogram at detecting lung injury.10 The nonanatomical straight edge effect is also evident on CT. Bronchoalveolar lavage fluid (BALF) findings are not specific, usually showing an increased number of leukocytes (predominantly lymphocytes). The majority of BAL lymphocytes postirradiation are CD4+. Lymphocyte numbers are increased in both the irradiated and nonirradiated lungs.5 Neutrophil, eosinophil, and macrophage numbers are also increased.
There are no proven therapies for radiation fibrosis, and there are no prospective controlled studies evaluating the efficacy of therapies for radiation pneumonia. However, many experts recommend the use of corticosteroids for symptomatic patients with a subacute onset of radiation lung injury.6,7,8,11 Prednisone (at least 60 mg/d) is generally given for two weeks, with a gradual taper over 3-12 weeks. Drugs that inhibit collagen synthesis, such as colchicine, penicillamine, IFN-g, or pirfenidone, may have the potential to modify the progression of the fibrosis that is a key histopathologic feature of radiation injury.
Drug-Induced Lung Injury
Many agents frequently used in the treatment of malignancy are associated with lung injury (see Table 3). The cytotoxic antibiotics (bleomycin and mitomycin) are commonly implicated. The nitrosoureas, methotrexate, alkylating agents (cyclophosphamide, busulfan, and chlorambucil), and the newer agents, such as the taxanes, are also responsible for a proportion of lung injury.
Some drugs, such as busulfan, have been associated with characteristic pathological changes (intracytoplasmic inclusions in the pulmonary endothelium).12 However, such changes are difficult to differentiate from inclusion due to viral infection. The pathology of the noninfectious pneumonias most often appear as either diffuse alveolar damage or interstitial inflammation with varying degrees of fibrosis.13 The former picture, consistent with ARDS, displays desquamation of the alveolar epithelium, interstitial and alveolar edema, and formation of hyaline membranes. The latter is characterized by widening of the interstitium with mononuclear cells and often progresses to diffuse fibrosis and honeycombing of the lung architecture.
| Table 3-Chemotherapeutic Agents Associated with Potential Lung Injury |
| Cytotoxic antibiotics |
| Bleomycin |
| Mitomycin |
| Dactinomycin |
| Alkylating agents |
| Cyclophosphamide |
| Busulfan |
| Chlorambucil |
| Ifosfamide |
| Antimetabolites |
| Methotrexate |
| Cytosine arabinoside |
| Fludarabine |
| Azathioprine |
| Nitrosoreas |
| Carmustine (BCNU) |
| Lomustine (CCNU) |
| Semustine (methyl-CCNU) |
| Miscellaneous agents |
| Doxorubicin |
| Procarbazine |
| Vinca alkaloids |
| Taxines |
| Paclitaxel |
| Docetaxel |
The diagnosis of drug-induced pulmonary toxicity is usually established clinically and is a diagnosis of exclusion. In some patients with a history of drug exposure and pulmonary dysfunction, bronchoalveolar lavage is used to exclude infection, while lung biopsy may be used to exclude lung involvement by malignancy. Cytological and histological findings due to cytotoxic drug-induced pulmonary toxicity usually are nonspecific.
Withdrawal of the drug is the initial step in management of drug-induced pulmonary toxicity. There are anecdotal reports of responses to corticosteroids after injury associated with many agents, but no controlled studies are available. Many experts recommend a therapeutic trial of prednisone at a dose of 1 mg/kg body weight among symptomatic patients. If no response is seen within several weeks, the corticosteroids may be tapered and stopped accordingly.
Conclusions
Noninfectious pulmonary complications of immunosuppression are most often related to complications of the underlying disorder, immunologically mediated, or acute lung injury secondary to systemic infection. Diagnostic testing rarely leads to specific treatment. The rationale behind evaluation of suspected noninfectious lung disease is exclusion of infection.
References
1. Grossman J, Kahn F. Noninfectious pulmonary disease in the immuno-compromised host. Sem Resp Med 1989;10:78-88.
2. Ognibene FP, et al. Adult respiratory distress syndrome in patients with severe neutropenia. N Engl J Med 1986;315:547-551.
3. Tenholder MF, Hooper RG. Pulmonary infiltrates in leukemia. Chest 1980;78:468-473.
4. Mah K, et al. Acute radiation-induced pulmonary damage: A clinical study on the response to fractionated radiation therapy. Int J Radiat Oncol Biol Phys 1987; 13:179.
5. Morgan GW, et al. Radiation and the lung: A reevaluation of the mechanisms mediating pulmonary injury. Int J Radiat Oncol Biol Phys 1995;31:361.
6. McDonald S, et al. Injury to the lung from cancer therapy: Clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys 1995;31:1187.
7. Nambu Y, Ohya N. Radiation pneumonia. In: Basic and Clinical Aspects of Pulmonary Fibrosis. Boca Raton, Fla.: CRC Press Inc.; 1994:445.
8. Rosiello RA, Merrill WM. Radiation-induced lung injury. Clin Chest Med 1990;11:65.
9. Rubin P, Casseratt GW, eds. Respiratory system. In: Clinical Radiation Pathology. Vol. 1. Philadelphia, Pa.: WB Saunders; 1968:423.
10. Ikezoe J, et al. CT appearance of acute radiation-induced injury in the lung. Am J Roentgenol 1988; 150:765.
11. Pickrell JA, Abdel-Mageed AB. Radiation-induced pulmonary fibrosis. In: Lung Biology in Health and Disease: Pulmonary Fibrosis. New York, N.Y.: Marcel Dekker, Inc.; 1995:363.
12. Cooper JAD, et al. Drug induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 1986; 133:321.
13. Sloane JP, et al. Histopathology of the lung after bone marrow transplantation. J Clin Pathol 1983;36: 546-554.
The rationale behind evaluation of suspected noninfectious lung disease in the immunocompromised host is:
a. exclusion of infection.
b. to find a specific treatment of the noninfectious injury.
c. never justifiable.
d. to determine lung inflammatory cytokine levels.
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