Pulmonary Disease in the Immunocompromised Host (Second of Two Parts)*

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1 Subject Review Pulmonary Disease in the Immunocompromised Host (Second of Two Parts)* WALTER R. WILSON, M.D., FRANKLIN R. COCKERILL III, M.D., Division of Infectious Diseases and Internal Medicine; EDWARD C. ROSENOW III, M.D., Division of Thoracic Diseases and Internal Medicine In this second segment of our article on pulmonary disease in the immunocompromised host (ICH), we review the infections associated with pulmonary in the ICH and the diagnostic approaches for both infectious and noninfectious conditions. Although certain Immunologie defects may predispose patients to specific infectious agents, virtually any infectious agent can cause pulmonary disease in any ICH. Physical findings and laboratory observations may give the clinician clues about probable causes of infection. Nevertheless, invasive diagnostic procedures in particular, open-lung biopsy are often necessary to diagnose pulmonary disease in the ICH. The relatively new technique of bronchoalveolar lavage is useful in diagnosing pulmonary disease in the patients with acquired immunodeficiency syndrome (AIDS). Further studies are necessary to confirm the reliability of this procedure as a diagnostic method in the ICH who does not have AIDS. In the first part of this article, we reviewed the various noninfectious pulmonary complications that can occur in the immunocompromised host (ICH), a person with an impaired immune system. In this second segment of our article, we will review the infections associated with pulmonary in the ICH and the diagnostic approaches to such conditions. As the life-span of the ICH has been extended, likewise the potential for exposure to nosocomial and opportunistic infections has increased. Use of stronger, more effective drugs has been associated with new drug-induced diseases that mimic pulmonary infections. In comparison with the past, however, more effective therapy, in particular antibiotics, is now available to treat complications in the ICH; thus, the correct diagnosis of such conditions is of utmost importance. Virtually any microorganism is capable of causing pulmonary in the ICH. Despite the numerous etiologic possibilities that must be considered in the differential diagnosis, recognition of the type of immunologic defect, epidemiologic factors, physical findings and clinical features, and laboratory The first part of this two-part article was published in the July issue of the Proceedings. Address reprint requests to Dr. W. R. Wilson, Division of Infectious Diseases and Internal Medicine, Mayo Clinic, Rochester, MN abnormalities may reduce this number to relatively few pathogens (Tables 1 and 11). Therefore, the physician can predict with reasonable accuracy the small group of microorganisms most likely responsible for the occurrence of pulmonary. TYPE OF IMMUNOLOGIC DEFECT Certain diseases are associated with abnormalities of the immune system that affect primarily T-lymphocytes, B- lymphocytes, granulocytes, or a combination of these systems. Moreover, the use of immunosuppressive or cytotoxic therapy may further depress immune function. Patients who have undergone splenectomy or those with quantitative or qualitative abnormalities of serum complement are also at risk for infections caused by certain microorganisms. Acute leukemia is typically associated with neutropenia (less than 5 neutrophiis/mm 3 ), lymphoma is associated with abnormalities of T-lymphocyte function, and chronic lymphocytic leukemia or multiple myeloma is associated with abnormalities of B-lymphocyte function. This "classic" concept of selective impairment of the immune system, however, should be interpreted with caution. Considerable crossover of immune dysfunction exists among patients with malignant lesions. Frequently, the ICH may have predominant dysfunction of a specific area of immunity, but the other immune systems are also Mayo Clin Proc 6:61-631,

2 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 611 Table 1. Important Considerations in the Diagnosis of Pulmonary Infiltrates in the Immunocompromised Host Type of immunologic defect Abnormal function of T-lymphocytes Abnormal function of B-lymphocytes Neutropenia Splenectomy Diminished serum complement Use of corticosteroid or cytotoxic therapy Epidemiologie factors History of infection History of travel or environmental exposure Use of drugs associated with cytotoxic pulmonary disease or history of radiotherapy Recent transfusion of blood or blood products Community-acquired pneumonitis Hospital-acquired pneumonitis Transplantation Homosexuality, hemophilia, abuse of intravenously administered drugs, Haitian origin, blood transfusion recipient (acquired immunodeficiency syndrome) Physical findings and clinical factors Skin lesions Infection of the head and neck Involvement of the central nervous system Diarrhea Laboratory findings Chest roentgenographic abnormalities Hypoxemia Abnormal liver function Mixed infection or superinfection usually impaired in some way. Nonetheless, categorization of infections most often associated with impairment of a specific type of immunity is useful in the initial approach to the ICH who has been found to have pulmonary (Table 11). EPIDEMIOLOGIC FACTORS History of Infection, Travel, and Environmental Exposure. "me physician should elicit an accurate history of possible exposure to mycobacterial infections or to endemic systemic mycoses such as histoplasmosis, coccidioidomycosis, or blastomycosis. The result of previous tuberculin skin testing is particularly important. The patient should be asked about travel to or previous residence in areas where certain systemic infections are epidemic, such as the southwestern United States (coccidioidomycosis) and the states in the Mississippi and Missouri river valleys (histoplasmosis). Primary pulmonary infection caused by mycobacteria or endemic systemic mycoses in the ICH have been described. 142,143 More commonly, pulmonary infection caused by these microorganisms in the ICH results from reactivation of a latent infection rather than a primary progressive infection. These microorganisms are most likely to be reactivated in patients who are receiving prolonged corticosteroid or cytotoxic therapy. 144 " 146 A history of foreign travel may suggest exposure to Strongyloides stercoralis or other enteric parasites. Possible zoonotic infections such as toxoplasmosis (from cats) or Chlamydia psittaci (from birds) should also be considered. Transfusion of Blood or Blood Products. Transfusion-associated infections occur relatively frequently in the ICH, but these infections are an uncommon cause of pulmonary. Hepatitis A or B, cytomegalovirus infection, Epstein-Barr virus infection, and toxoplasmosis may result from transfusion of contaminated blood products. 147 Of these, cytomegalovirus infection is most often associated with pulmonary. The acquired immunodeficiency syndrome (AIDS) also may be associated with transfusion of blood or blood products. Pulmonary edema and leukoagglutinin reactions are more common causes of transfusion-associated pulmonary than are these microorganisms. Community-Acquired or Hospital-Acquired Pneumonitis. Although substantial overlap has been found between community-acquired and hospital-acquired pneumonitis, microorganisms can be considered as more likely associated with one or the other means of acquisition (Table 12). Although Legionella and Pneumocystis carinii pneumonitis are most often community-acquired infections, nosocomial outbreaks have been occasionally described. 148 ' 149 The time of onset of infection in the ICH influences the microbiologic spectrum of disease. For example, pneumonitis in neutropenic patients with leukemia who have received no cytotoxic chemotherapy is most often community acquired and is usually caused by Staphylococcus aureus or Streptococcus pneumoniae. In neutropenic patients with leukemia who have received the first or second course of cytotoxic drugs, pneumonitis caused by S. aureus is still more common than that caused by Pseudomonas aeruginosa or other nosocomially acquired gram-negative bacilli. 15 With longer hospitalization and additional chemotherapeutic attempts to induce remission, however, nosocomial pneumonitis caused by P. aeruginosa or other gram-negative bacilli (such as Klebsiella or Serratia) or fungi (such as Aspergillus or Zygomycetes) predominates. Colonization by Candida occurs frequently after prolonged hospitalization, and disseminated candidiasis is especially common in neutropenic patients. Candida pneumonitis is rare, and isolation of Candida from bronchopulmonary specimens usually is associated with aspiration or colonization rather than invasive pulmonary infection. Untreated patients with lymphoma or Hodgkin's disease are at risk for community-acquired bacterial pneumonia and crypto-

3 612 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 Table 11. -Type of Immunologie Defect or Related Factor and Associated Microorganisms Microorganism Defect or factor Bacteria Fungi Viruses Parasites Abnormal T-lymphocyte function Abnormal B-lymphocyte function Neutropenia (<5 neutrophi Is/mm 3 ) Splenectomy Decreased serum complement Use of corticosteroid therapy equivalent to >2 mg of prednisone daily or cytotoxic therapy (or both) Listeria monocytogenes Nocardia Salmonella (species other than typhi) Mycobacteria teg/one//a Streptococcus pneumoniae Haemophilus influenzae Pseudomonas aeruginosa Escherichia coli Klebsiella Serratia Aeromonas Other gram-negative bacilli 5. pneumoniae H. influenzae E. coli Staphylococcus aureus Neisseria meningitidis S. pneumoniae H. influenzae Neisseria spp. 5. aureus L. monocytogenes Mycobacteria P. aeruginosa Nocardia Other gram-negative bacilli Cryptococcus Histoplasma Coccidioides Blastomyces Trichosporon Aspergillus Zygomycetes Aspergillus Zygomycetes H. capsulatum C. neoformans C. immitis neoformans capsulatum immitis dermatitidis Cytomegalovirus Varicella-zoster Herpes simplex Cytomegalovirus Varicella-zoster Herpes simplex Pneumocystis carinii Toxoplasma gone/// Strongyloides stercoralis P. carinii T. gondii Strongyloides stercoralis coccal or mycobacterial infections. Among patients with lymphoma who have undergone cytotoxic therapy, P. carinii, cryptococcal, P. aeruginosa, and viral (varicellazoster and herpes simplex) infections predominate. Transplantation. Renal. Pneumonitis that occurs in recipients of renal transplants can be categorized into cases that develop within the first month postoperatively, from 1 to 4 months postoperatively, or later than 4 months after transplantation (Table 13). 15 During the first month after renal transplantation, pulmonary infections are usually related to aspiration, bacteremia caused by wound sepsis, or infection associated with intravascular lines The most critical period for life-threatening infection among renal transplant patients is from 1 to 4 months after transplantation, primarily because immunosuppresacquisition Community Hospital Table 12. Community-Acquired or Hospital-Acquired Pneumonitis Microorganism Bacteria Fungi Viruses Parasites Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Legionella* Mycobacteria Nocardia Mycoplasma Chlamydia Pseudomonas aeruginosa S. aureus Other gram-negative bacillit Cryptococcus neoformans Histoplasma capsulatum Coccidioides immitis Blastomyces dermatitidis Trichosporon Aspergillus Zygomycetes *Nosocomial infections may also occur from these microorganisms. tespecially associated with aspiration. Varicella-zoster Herpes simplex Cytomegalovirus Influenza Pneumocystis carinii" Strongyloides Toxoplasma gondii

4 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 613 Table 13. Causes of Pneumonitis After Renal Transplantation Period after transplantation <1 month 1-4 months >4 months Aspiration Wound infection or intravascularline colonization Cytomegalovirus Herpes simplex Varicella-zoster Pneumocystis carinii Aspergillus Zygomycetes Nocardia Mycobacteria Adenovirus Cryptococcus neoformans P. carinii Legionella sive therapy is usually most intensive during that time. During the first few weeks after transplantation, T-cellmediated immunity reaches a nadir, and it does not begin to return to near-normal levels until 3 to 4 months later. Cytomegalovirus, a common cause of infection in renal transplant patients, occurs most frequently 1 to 4 months after transplantation. 156 " 161 Although many organ systems, including the lungs, may become involved during the course of cytomegalovirus disease, a self-limited febrile illness is the sole manifestation in most patients. Cytomegalovirus infection in renal transplant patients results from (1) transmission of cytomegalovirus from a seropositive donor to a seronegative recipient via the kidney allograft or transfused whole blood or (2) reactivation of latent cytomegalovirus in a recipient who was seropositive before transplantation. The chest roentgenogram in patients with cytomegalovirus pneumonia usually demonstrates a bilateral, symmetric, diffuse interstitial process that primarily involves the lower lobes. 162 In most patients, the pulmonary involvement is not severe and respiratory failure is uncommon. The pulmonary process may progress during a period of several days. Acute respiratory failure that develops in less than 12 hours is usually not caused by cytomegalovirus but more likely by a bacterial or fungal infection. 15 Cytomegalovirus infection further suppresses T-cellmediated immunity and may also cause severe neutropenia. Accordingly, cytomegalovirus infection may be associated with severe pulmonary superinfection caused by P. carinii, Aspergillus, or Cryptococcus neoformans. Superinfection caused by these microorganisms should be suspected in patients with cytomegalovirus infection in whom severe, progressive, life-threatening pulmonary disease develops. A rapidly lethal form of cytomegalovirus infection has been described in patients who have undergone renal transplantation; it is characterized by fever, leukopenia, and rapid onset of severe pulmonary and hepatic dysfunction in association with gastrointestinal hemorrhage, multiple organ-system failure, and death, often from superinfection caused by bacteria, fungi, or protozoa. 163 Herpes simplex virus is second in frequency only to cytomegalovirus as a cause of infection in renal transplant patients. 15 Although mucocutaneous lesions occur frequently, disseminated herpes simplex is uncommon, and primary herpes simplex pneumonia is rare after renal transplantation. In approximately 1% of renal transplant patients, varicella-zoster infection develops after transplantation. 15 Dermatomal varicella-zoster infections rarely disseminate or cause pneumonitis postoperatively in these patients. Primary varicella-zoster infection in nonimmune persons is a serious infection after renal transplantation and may cause life-threatening pneumonia. Prophylactic treatment with zoster immune serum globulin is important in nonimmune renal transplant patients who are exposed to varicella-zoster infection. Adenovirus pneumonia is more common in renal transplant patients than it is in other immunosuppressed patients. 164 ' 165 In renal transplant patients, C. neoformans is the most common fungal infection and is the most frequent cause of infection of the central nervous system. Virtually all such infections occur more than 4 months postoperatively. 15 Approximately a third of the patients with cryptococcosis of the central nervous system have concomitant pulmonary infection. All patients with C. neoformans isolated from cultures of bronchopulmonary secretions should undergo cerebrospinal fluid examination. Aspergillus is the second leading cause of fungal infection in renal transplant patients; such infections usually occur from 1 to 4 months postoperatively. Aspergillus superinfections are especially likely to occur in neutropenic patients in association with cytomegalovirus infection. P. carinii pneumonitis usually occurs during the second to sixth month after renal transplantation. 15 Frequently, cytomegalovirus and P. carinii infections occur concurrently.

5 614 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 Table 14. Causes of Pulmonary Infiltrates After Bone Marrow Transplantation <3 days Pseudomonas aeruginosa Aspiration (gram-negative bacilli, anaerobes) Period after transplantation 3-1 days Cytomegalovirus Pneumocystis carinii Other viruses Other factors* > 1 days Streptococcus pneumoniae Staphylococcus aureus Varicella-zoster Craft-versus-host disease *Drug-induced pulmonary disease, radiation pneumonitis, edema, hemorrhage, graft-versushost disease. Bone Marrow. The cause of infection in bone marrow transplant patients depends on the time of onset after transplantation (Table 14). Infections that occur within 3 days after bone marrow transplantation are related to neutropenia, which is most severe during this period. 166 Gram-negative bacterernia, especially that caused by Escherichia coli or Pseudomonas, occurs frequently during this period. Bacterial pneumonia, however, during the first 3 days after transplantation is relatively uncommon and, when present, is usually related to aspiration pneumonitis. Pneumonitis is most likely to occur from 3 to 1 days after bone marrow transplantation and is most often caused by cytomegalovirus or other viruses (such as adenovirus, papovavirus, and enterovirus). 167 "' 69 Because most bone marrow transplant recipients receive trimethoprim-sulfamethoxazole prophylaxis, P. carinii infections occur infrequently. The predominance of these microorganisms during this period corresponds to the intensity of immunosuppressive therapy and diminished T-cell immunity. Hypoxemia commonly occurs in conjunction with cytomegalovirus or pneumonitis caused by P. carinii. Pneumonitis that occurs more than 1 days after bone marrow transplantation is related to residual deficiency of the immune system and to the additional immunosuppressive effects of graft-versus-host disease and its treatment. 166 Cutaneous varicella-zoster infection, with or without pulmonary involvement, is the most common late infection that occurs in bone marrow transplant patients. Varicella-zoster infection develops in approximately 5% of bone marrow recipients who have had such an infection previously; the median time of onset is 5 months after transplantation. 166 Primary varicella-zoster infection or dissemination of cutaneous varicella-zoster, which occurs relatively commonly in bone marrow transplant patients, is associated with a high mortality. Pneumonitis caused by 5. pneumoniae or S. aureus occurs less frequently than does varicella-zoster infection and, when present, is associated with chronic graftversus-host disease. Presumably, the increased susceptibility to encapsulated gram-positive cocci is the result of diminished opsonizing antibodies in these bone marrow recipients.' 7 Acquired Immunodeficiency Syndrome. Major risk groups in which AIDS has occurred include homosexual and bisexual men, abusers of intravenously administered drugs, Haitians, and hemophiliacs. Sporadic cases of AIDS have been reported in patients who have received multiple blood transfusions and in spouses and children of persons with AIDS. 171 " 175 The specific immunoincompetence noted in AIDS is a decrease in the absolute number of circulating helper T-lymphocytes (OKT4) in association with a relative or absolute increase in suppressor T-lymphocytes (OKT8), a situation that results in a decreased ratio of helper to suppressor T-lymphocytes. 87 ' 76 The acquired suppression of helper T-lymphocytes in patients with AIDS is the result of a retrovirus infection.' 77 '' 78 Recently, B- lymphocyte dysfunction has also been detected. In many patients with AIDS, serum immunoglobulins increase nonspecifically. An abnormal "hyper B-cell response" to large reactive Ivmph nodes and aggressive extranodal B-cell lymphomas have been reported. 179 Severe (often fatal) pulmonary infections occur frequently in patients who have AIDS. The most common microorganisms that cause pulmonary infection in these patients are P. carinii, mycobacteria (especially Mycobacterium avium-intracellulare complex), C. neoformans, and cytomegalovirus. 18 " 184 Less common causes of pulmonary infections in these patients are Nocardia asteroides, Toxoplasma gondii, herpes simplex, S. stercoralis, Cryptosporidium spp., and other fungi such as Aspergillus, Zygomycetes, Histoplasma capsulatum, and Coccidioides immitis. Concomitantly occurring infections caused by two or more microorganisms are common among patients with AIDS. PHYSICAL FINDINGS AND CLINICAL FACTORS The occurrence of cutaneous lesions in association with pneumonitis suggests the presence of certain groups of microorganisms (Table 15). In neutropenic patients, P. aeruginosa infection is associated with vasculitic cutaneous lesions known as ecthyma gangrenosum. The lesion

6 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 615 Table 15. Causes of Pulmonary Infiltrates in Immunocompromised Patients With Various Conditions Condition Bacteria Fungi Viruses Parasites Cutaneous lesions Infections of the central nervous system Infections of the head and neck Modified from Young LS. Staphylococcus aureus Pseudomonas aeruginosa Aeromonas hydrophila Nocardia Mycobacteria Vibrio alginolyticus Streptococcus pneumoniae S. aureus Nocardia P. aeruginosa Mycobacteria teg/one//a Haemophilus influenzae Neisseria Croup A ß-hemolytic streptococci and anaerobes (Ludwig's angina) P. aeruginosa H. influenzae Cryptococcus neoformans Blastomyces dermatitidis Aspergillus Coccidioides immitis Zygomycetes Trichosporon C. neoformans Zygomycetes Aspergillus C. immitis Aspergillus Zygomycetes Histoplasma capsulatum Varicella-zoster Herpes simplex Varicella-zoster Herpes simplex Cytomegalovirus (retinal lesions) Herpes simplex Cytomegalovirus (retinitis) Toxoplasma gondii Strongyloides stercoralis begins as an erythematous macule, which becomes indurated and may vesiculate. The bullous lesions ulcerate and evolve into a black necrotic area that is surrounded by ecchymosis and erythema (Fig. 5 upper left). Ecthyma gangrenosum lesions are often located in the perirectal and vaginal areas, and the usual portal of entry is a perirectal ulcer or fistula. Less commonly, ecthyma gangrenosum may occur on the trunk or extremities and may resemble pyoderma gangrenosum or other cutaneous infections. The initial mechanism responsible for ecthyma gangrenosum seems to be venous thromboses caused by invasion of blood vessels by P. aeruginosa^86 (Fig. 5 upper middle). Other gram-negative bacilli that have been associated with skin lesions in neutropenic patients include Aeromonas hydrophila, Vibrio alginolyticus, and some Enterobacteriaceae. Aeromonas skin lesions may resemble those caused by P. aeruginosa (Fig. 5 upper right). These lesions, which are usually located on the extremities, are slowly evolving and erythematous with a violaceous hue. S. aureus and Nocardia may cause pneumonitis and subcutaneous abscesses in patients with bacteremia. Mycobacteria (especially M. avium-intracellulare complex) may result in extensive, necrotic cutaneous lesions, particularly in patients with AIDS (Fig. 5 lower left). In neutropenic patients, fungal infections associated with pulmonary and skin lesions are most often caused by Aspergillus or Zygomycetes. Trichosporon cutaneous infections in neutropenic patients result in extensive, slowly evolving necrotic lesions that resemble necrotic cutaneous lesions associated with warfarin sodium therapy (Fig. 5 lower middle). In patients with T-cell abnormalities, such as those with Hodgkin's disease, cutaneous cryptococcal lesions may develop (Fig. 5 lower right). Uncommonly, fungal pneumonitis and chronic skin lesions may develop as a result of reactivation of a systemic mycosis, such as blastomycosis. Although disseminated Candida infection with skin lesions occurs relatively commonly in neutropenic patients, it rarely, if ever, causes pneumonitis. The cutaneous lesions associated with disseminated varicella-zoster or herpes simplex infection are easily recognizable. Pulmonary Infiltrates and Infection of the Central Nervous System. The most common microorganisms isolated from immunocompromised patients with infections of the central nervous system are shown in Table 15. Neutropenic patients are at greatest risk for meningoencephalitis or a brain abscess caused by P. aeruginosa or other gram-negative bacilli, Aspergillus, Zygomycetes, and S. aureus. P. aeruginosa and Aspergillus are common inhabitants of the external auditory canal in neutropenic patients, and direct extension to the central nervous system may occur (Fig. 6). Disseminated Candida infection may cause meningitis or retinitis but, as previously mentioned, rarely causes pulmonary. Disseminated infection due to M. avium-intracellulare complex may cause skin lesions and pneumonitis in patients with AIDS 183 ' 184 (Fig. 5 lower left). In the ICH with primarily T-cell dysfunction, pneumonitis, and central nervous system involvement, C. neoformans, Nocardia, mycobacteria, and varicella-zoster are the most common causative microorganisms (Table 15).

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8 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 617 Fig. 6. Computed tomographic scan of head, showing Aspergillus brain abscess caused by extension of otitis externa. Although Listeria monocytogenes is a relatively common cause of meningitis in these patients, it rarely causes pulmonary. Cytomegalovirus may cause retinitis as a late complication in renal transplant recipients, but cytomegalovirus pneumonitis usually precedes retinitis rather than occurring synchronously with it. Similarly, Toxoplasma is a cause of meningoencephalitis in patients with abnormal T-cell function but usually does not cause concomitant pneumonitis. 5. stercoralis is a rare cause of concurrent central nervous system and pulmonary infections, including severe bronchitis. 187 In patients with B-cell abnormalities or who have undergone splenectomy, pneumonitis and meningitis are most often caused by 5. pneumoniae or Haemophilus influenzae (or rarely by Neisseria species). Postoperative wound infections, bacteremia, pulmonary, and infections of the central nervous system are usually caused by 5. aureus or nosocomially acquired gram-negative bacilli. Pulmonary Infiltrates and Infections of the Head and Neck. An especially aggressive form of oropharyngeal infection caused by group A ß-hemolytic streptococci and anaerobes of the mouth (Ludwig's angina) may occur in neutropenic patients and result in mediastinitis and acute respiratory tract obstruction (Table 15) (Fig. 7). In patients who have undergone splenectomy or those with diminished B-cell immunity, acute epiglottiditis and airway obstruction due to H. influenzae may develop. The role of P. aeruginosa and Aspergillus in neutropenic patients with otitis externa and extension of the infection to the central nervous system was discussed in the previous section. In neutropenic patients with black necrotic oropharyngeal or ophthalmic lesions, especially those occurring in association with cavernous sinus thrombosis, Zygomycetes infection should be suspected. Oropharyngeal candidiasis is common in neutropenic patients and in those with abnormal T-cell function, and aspiration of oropharyngeal secretions frequently occurs. Patients with disseminated hjstoplasmosis often have ulcerative lesions of the tongue or oral cavity. Herpes simplex causes vesiculopustular lesions of the oral cavity and may be associated with pulmonary. Pulmonary Infiltrates Associated With Diarrhea. In the ICH with pneumonitis that is associated with diarrhea, infection caused by Legionella, herpes simplex, Strongyhides, Cryptosporidium spp., or cytomegalovirus should be suspected. Hemorrhagic colitis associated with cytomegalovirus infection has been described. 163 Herpes simplex is a common cause of proctitis in patients with AIDS and rarely may be associated with disseminated infections. A history of foreign travel is an important epidemiologic clue in patients with Strongyloides infection. LABORATORY FINDINGS Chest Roentgenographic Abnormalities. The chest roentgenographic appearance and the rate of progression of pulmonary are useful clues to the cause of pulmonary in the ICH. Evidence of consolidation and lobar, nodular, or patchy involvement on a chest roentgenogram suggests bacterial or fungal infection, thromboembolic disease, pulmonary edema, hemorrhage, or tumor. Diffuse bilateral interstitial Fig. 5. Findings associated with pulmonary lesions in the immunocompromised host. Upper Left, Ecthyma gangrenosum lesions in vaginal area. Upper Middle, Venous thrombosis as etiologic factor in ecthyma gangrenosum. Vessel wall had been invaded by Pseudomonas aeruginosa. Upper Right, Aeromonas hydrophila skin lesions. Lower Left, Skin lesions caused by Mycobacterium avium-intracellulare complex in patient with acquired immunodeficiency syndrome. Lower Middle, Trichosporon skin lesions. Lower Right, Cryptococcus neoformans skin lesion.

9 618 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 Fig. 7. Roentgenogram of patient with Ludwig's angina, showing gas in soft tissues. suggest the presence of a P. carinii, mycobacterial, fungal (Aspergillus or Zygomycetes), or viral (especially cytomegalovirus) infection; lymphangitic spread of tumor; drug-induced pulmonary disease; radiation pneumonitis; or leukoagglutinin reaction. The rate of progression of the pulmonary process is especially useful in determining the cause of pulmonary (Table 16). 146 An acute process that evolves during a 24-hour period or less suggests bacterial pneumonia, pulmonary emboli or edema, hemorrhage, or leukoagglutinin reaction. A subacute process that evolves during a period of a few days to a week suggests the presence of a viral (Pneumocystis), fungal (Aspergillus, Zygomycetes, or Cryptococcus), or bacterial (Legionella, Mycobacterium, or Nocardia) infection. A chronic course that evolves during 1 or more weeks suggests a mycobacterial or fungal infection, such as a systemic mycosis (for example, histoplasmosis or coccidioidomycosis). Hypoxemia. Another useful clue to the diagnosis of pulmonary infection in the ICH is the measurement of arterial partial pressure of oxygen. 146 Most pulmonary infections caused by bacteria (excluding Mycobacterium or Nocardia), viruses, and P. carinii are associated with a diminished arterial partial pressure of oxygen (less than 65 mm Hg, measured while the patient is breathing room air). Contrariwise, patients with pneumonia caused by Mycobacterium, Nocardia, and most fungi usually have values that exceed 7 mm Hg in room air. The typical manifestations of P. carinii pneumonia in a patient who does not have AIDS and is receiving high-dose corticosteroid therapy, with or without cytotoxic therapy, are hypoxemia (arterial partial pressure of oxygen of less than 65 mm Hg) and a chest roentgenogram that may disclose either normal findings or diffuse interstitial. For unknown reasons, Pneumocystis infection is less often associated with hypoxemia in patients with AIDS than in other patients. Elevation of Hepatic Enzymes. The causes of pulmonary associated with elevated levels of hepatic enzymes are shown in Table 17. Cytomegalovirus is the most common infection responsible for hepatitis and pulmonary. Nocardia, S. aureus, and Pseudomonas also frequently cause hepatic abscess and subsequent elevation of concentrations of liver enzymes. Mixed Infection or Superinfection. At least 1% of immunocompromised patients with pulmonary have an infection caused by multiple microorganisms. 58,146 ' 188 Patients with AIDS are especially likely to Table 16. Rate of Progression of Infectious Pulmonary Infiltrates on Chest Roentgenogram and Potential Underlying Organisms Acute Subacute Chronic Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Pseudomonas aeruginosa Modified from Rubin RH, Greene R.' Pneumocystis carinii Aspergillus Zygomycetes Cryptococcus neoformans Herpes simplex Varicella-zoster Nocardia Mycoplasma Cytomegalovirus Influenza virus Legionella Mycobacteria Mycobacteria Coccidioides immitis Histoplasma capsulatum Blastomyces dermatitidis Strongyloides stercoralis

10 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 619 Table 17. Causes of Pulmonary Infiltrates Associated With Elevated Levels of Hepatic Enzymes Cytomegalovirus Legionella Nocardia Staphylococcus aureus Pseudomonas aeruginosa Mycobacteria Histoplasma capsulatum Toxoplasma gondii by gram-negative bacilli, especially Pseudomonas and antibiotic-resistant Enterobacteriaceae. P. aeruginosa is a common cause of superinfection in patients with 5. aureus pneumonitis; however, 5. aureus is a rare cause of superinfection in patients who have had a P. aeruginosa infection. Aspergillus or Zygomycetes are common causes of pulmonary superinfection in neutropenic patients. Early recognition, a high index of suspicion, and prevention are important factors in surveillance of the ICH for impending pulmonary superinfection. have mixed pulmonary infections. Combinations of microorganisms that frequently occur in the immunocompromised patients are shown in Table 18. Superinfections probably occur more commonly than do mixed infections. Superinfections should be suspected in the following patients: (1) those who have a satisfactory initial clinical response to therapy and then experience an abrupt or subacute deterioration, (2) patients whose condition deteriorates despite appropriate therapy, (3) patients with neutropenia, and (4) patients who have received prolonged high-dose immunosuppressive therapy (more than 2 mg of prednisone daily or an equivalent regimen). In one study, pulmonary superinfection occurred in 43% of renal transplant patients and accounted for 81% of the fatalities among these patients. 58 All but 1 of the 23 patients with superinfection in that series died. After renal transplantation in that study, pulmonary superinfection occurred most commonly among three groups of patients: (1) those with pulmonary emboli, (2) those with cytomegalovirus infection, and (3) patients with neutropenia, especially those who were receiving high-dose corticosteroid therapy. Although nonimmunosuppressed patients with a pulmonary embolus rarely have a secondary infection, more than 5% of immunocompromised patients and 89% of renal transplant patients have a secondary pulmonary infection after pulmonary thromboembolism. 58 The microorganisms responsible for superinfections differ somewhat from those that cause primary infections. Virtually all cases of bacterial superinfection are caused Table 18. Combinations of Microorganisms That Frequently Cause Pulmonary Infiltrates in Immunocompromised Patients Cytomegalovirus and Pneumocystis carinii Cytomegalovirus and gram-negative bacilli (especially Pseudomonas aeruginosa) Cytomegalovirus and Cryptococcus neoformans C. neoformans and Nocardia C. neoformans and P. carinii Nocardia and Aspergillus Aspergillus and Pseudomonas aeruginosa DIAGNOSTIC APPROACHES As we have discussed, numerous causes exist for pulmonary in immunocompromised patients. Moreover, as mentioned earlier, in a single patient more than one cause may be responsible for pulmonary at any one time. Although no symptom complex or physical findings are indicative of a specific cause, the clinician should nevertheless obtain an accurate medical history and perform a complete physical examination. The type and duration of symptoms and signs may provide clues about the diagnosis. For example, fever with acute dyspnea, chest pain, and hemoptysis in association with a pulmonary friction rub might suggest pulmonary embolus or vasculitis, whereas fever with acutely worsening dyspnea, a nonproductive cough, and normal breath sounds in a patient who is receiving corticosteroids might suggest an infection with P. carinii. A discussion about signs and symptoms associated with specific conditions in the ICH was presented in the first part of this article. One pathologic process that should be reemphasized is pulmonary edema. Patients who have undergone cardiac or renal transplantation may have fever related to organ rejection and pulmonary as a result of interstitial edema due to decreased performance of the transplanted heart or kidney. The physician should carefully examine any ICH for signs of fluid overload and compare current and prior body weights. If he is still uncertain, empiric administration of a moderately potent diuretic might be diagnostic. In the seriously ill ICH with pulmonary disease, the goal is to achieve a specific etiologic diagnosis expediently and safely. An adequate sample of lung tissue is needed for histologic examination, microbial stains, and cultures so that appropriate therapy may be instituted promptly. Although open-lung biopsy is generally the most dependable procedure for achieving this goal, this approach should not be used initially in patients with AIDS and recipients of orgran transplants during the immediate postoperative period. In patients with AIDS, bronchoscopy with bronchoalveolar lavage and brush or forceps biopsy of the lung may be adequate for diagnosis

11 62 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 because pulmonary usually are limited to infections (such as P. carinii or cytomegalovirus infections) that manifest with high concentrations of organisms. 189 " 191 Some febrile patients with AIDS, despite severe pulmonary disease, do not have pulmonary symptoms and, moreover, have normal findings on chest roentgenograms. In this setting, an increased alveolar-arterial oxygen gradient at rest, further arterial oxygen desaturation during exercise, low carbon monoxide diffusing capacity of the lungs (less than 8% of the predicted mean normal value), and grade 3 or 4 uptake of gallium radionuclide in the lungs suggest P. carinii pneumonia. 171,192 In patients who have undergone heart, heart and lung, liver, or kidney transplantation, bacterial pulmonary infections are common in the immediate postoperative period (within 1 month postoperatively). These infections may be diagnosed with noninvasive procedures or may be managed empirically with broadspectrum antimicrobial agents. In the immunocompromised patient with pulmonary, prolonged surveillance is inappropriate. Tests that are less invasive than open-lung biopsy may yield misleading or inadequate results, and the consequence may be incorrect or only partially correct therapy. In this setting, the patient would continue to deteriorate and subsequently might be too ill to undergo what is likely the best method for diagnosis, open-lung biopsy. Empiric Management. The empiric use of broadspectrum antimicrobial agents in the ICH with pulmonary who does not have AIDS may be beneficial. If the patient's condition improves on such a regimen, the physician may still be uncertain about the duration of treatment because guidelines have not been published. A "reasonable" period of observation might be 24 to 72 hours. The approach that is usually followed at our institution is shown in Figure 8. If pulmonary progress or the patient shows signs of clinical deterioration during empiric therapy, invasive diagnostic procedures should be done. The recommended empiric antimicrobial regimen (cephalosporin, aminoglycoside, antipseudomonal penicillin, and erythromycin) provides coverage against most gram-negative and gram-positive coccal and bacillary bacteria, Legionella, and Chlamydia. If the patient is receiving chemotherapeutic agents or corticosteroids, the addition of trimethoprim-sulfamethoxazole is recommended, which is effective against Pneumocystis and Nocardia. We do not use amphotericin or other antifungal agents or antiviral agents as empiric therapy. The associated toxicity and expense of these additional antimicrobial agents are not justified. The cost of empiric antimicrobial therapy for immunocompromised patients with pulmonary at our institution is shown in Table 19. Also shown are the costs of bronchoscopy and open-lung biopsy. The empiric use of antituberculous drugs should be considered in patients with a history of exposure to or infection with M. tuberculosis or with a positive tuberculin skin test. The physician must remember that immunosuppressed patients may not have a reactive tuberculin skin test despite active disease. If the patient has AIDS, then trimethoprim-sulfamethoxazole alone or in conjunction with erythromycin can be used. Empiric antimicrobial therapy in patients with AIDS, however, has potential risks, such as the development of intolerable rashes or cytopenias especially with the use of trimethoprim-sulfamethoxazole. 193,194 In addition to understanding the principles of empiric management, the physician should be aware of the conventional noninvasive and contemporary invasive methods, including open-lung biopsy, used for diagnosing pulmonary in immunocompromised patients. Consequently, in the subsequent section, we discuss these diagnostic approaches (in order of increasing complexity) and the advantages and disadvantages of each method. Noninvasive Diagnostic Prcedures. Analysis of Sputum Specimens. The collection of sputum, whether spontaneously produced or induced with a bronchial irritant, for staining and cultures should be encouraged in any patient with a cough or chest roentgenographic abnormalities, regardless of the immune status. Occasionally, sputum may be suctioned by means of a nasotracheal catheter. The results of aerobic bacterial and fungal cultures with specimens obtained by using any of these methods must be interpreted with caution. The oropharynx and upper respiratory tract of immunosuppressed patients may be colonized with gram-negative aerobic bacteria, 5. aureus, Candida species, occasionally saprophytic fungi (such as Aspergillus species), and rarely C. neoformans, N. asteroides, or atypical mycobacteria. Cytomegalovirus or herpes simplex may be present with or without oropharyngeal disease and may contaminate pulmonary viral cultures. Because these organisms may contaminate the sputum as it passes through the oropharynx, the validity of subsequent culture isolates is questionable. For direct examination of sputum, a Gram stain should be performed. If few squamous epithelial cells (fewer than 1 per low-power field) or many polymorphonuclear leukocytes (more than 25 per low-power field) or both are seen, the specimen most likely is expectorated sputum and not saliva. 195 The physician should remember, however, that in the ICH who is severely neutropenic but able to produce sputum, few or no polymorphonuclear leukocytes may be observed on a Gram stain.

12 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 621 Generally, such patients produce little or no sputum. A negative Gram stain does not rule out bacterial pneumonia, nor does a positive Gram stain specifically indicate the diagnosis of bacterial pneumonia. The presence of many bacteria with similar morphologic features may suggest a specific bacterial pathogen. Direct examination of a potassium hydroxide preparation of sputum with use of phase-contrast microscopy may be valuable for rapid identification of yeast forms of dimorphic fungal pathogens, especially Blastomyces dermatitidis. A positive acid-fast or auramine-rhodamine stain of sputum implies pulmonary mycobacterial infection in the ICH until disproved by culture (some mycobacteria may be contaminants), and appropriate therapy should be initiated. A direct fluorescent antibody examination for Legionella can be performed on sputum and may be positive in a third of all cases eventually proved by culture. 196 A direct examination of concentrated sputum in combination with a stool examination may be helpful for diagnosing S. stercoralis infection. Occasion- Discontinue cytotoxic drugs Physical examination If pulmonary edema suspected- - diuresis Laboratory studies Sputum (spontaneous or induced) Gram stain, aerobic bacteria culture Legionella direct fluorescent antibody study, culture Phase-contrast examination, fungal culture Acid-fast bacilli stain, mycobacteria culture Silver stain for Pneumocystis carinii (?) (AIDS only) Blood cultures Bacteria, mycobacteria, fungi Serology (?) CMV, furigi, Legionella Other (if chest x-ray normal but pulmonary symptoms present) Gallium scan (?) e.g., dyspnea in patients with AIDS V/Q scanning (?) e.g., dypsnea, chest pain AIDS TMP-SMX ± erythromycin Empiric therapy (24-72 h) Other Cephalosporin + aminoglycoside + anti-pseudomonas penicillin + erythromycin ± TMP-SMX* AIDS Transbronchia, lavage and biopsy ( + ) Improvement: treat for days No improvement or worsening (-) S pecific therapy Other Open-lung biopsy Addition is recommended in patients receiving chemotherapeutic agents or corticosteroids. Fig. 8. Diagnostic and therapeutic approach for pulmonary disease in immunocompromised patients. The high incidence of side effects to antimicrobial agents in patients with AIDS may preclude their empiric use. AIDS = acquired immunodeficiency syndrome; CMV = cytomegalovirus; TMP-SMX = trimethoprim-sulfamethoxazole; V/Q = ventilation-perfusion.

13 622 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 Table 19. Comparative Costs of Empiric Antimicrobial Therapy, Bronchoscopy, and Open-Lung Biopsy in Immunocompromised Patients With Pulmonary Infiltrates (January 1985, Mayo Clinic) Cost (drug* + Antimicrobial agent Dosage Route admir listrationt) Cefazolin Ticarcillin Centamicin Trimethoprimsulfamethoxazole Erythromycin Amphotericin B Acyclovir Isoniazid Rifampin Itemized charges Operating room Physician (bronchoscopi Anesthesiologist Microbiology/pathology Total 1 g every 8 h 3 g every 4 h 1 mg every 8 h 2 mg/kg (trimethoprim equivalent) or 35 mg every 6 h 5 mg every 6 h 2 mg/day 35 mg every 8 h 3 mg orally/day 6 mg orally/day Bronchoscopy and biopsy* $ 225. st or surgeon) 35. services 487. $1,62. Intravenous $ Intravenous Intravenous Intravenous Intravenous Intravenous Intravenous Oral Oral Open-lung biopsy $ $2,182. Calculated for 2-week course of therapy in 7-kg patient. tlntravenous piggyback = $1.75, and oral administration = $.55/pill or capsule. isame charge whether bronchoscopic lavage or biopsy , , , ally (and more often if an induced sputum specimen is used), silver or toluidine blue stains of sputum will show P. carinii organisms in patients with an extremely dense infection, such as in patients with AjDS. Disseminated fungal or mycobacterial, cytomegalovirus, or P. carinii infections may manifest with interstitial but little or no sputum production. Sputum cultures may eventually yield the following organisms, which should always be considered pathogens: Legionella species, M. tuberculosis, and dimorphic fungi (H. capsulatum, B. dermatitidis, C. immitis, and Sporothrix schenckii). In sputum cultures, the isolation of many pathogens may entail days to weeks (Table 2). As mentioned previously, the isolation of C. neoformans, N. asteroides, or atypical mycobacteria from sputum may result from colonization of the oropharyngeal airway and thus may not indicate the presence of infection. Serology. Results of serology cannot predictably establish or exclude a specific agent as a cause of pulmonary disease in the ICH. Because of immune suppression, the ICH may not have a serologic response despite the presence of active disease. The detection and quantification of IgG antibodies obtained from serum at the onset of clinical illness occasionally are beneficial for diagnosing infection with the following organisms: C. trachomatis, cytomegalovirus, Legionella species, and 7. gondii. Serum IgM antibodies can be identified for cytomegalovirus and T. gondii and may be detected sooner (that is, during acute disease) than IgG antibodies but they are generally present only in primary infections with these organisms. Serologic tests in convalescing patients (serum IgG antibodies studied 3 to 4 weeks after the onset of clinical illness) are often necessary to establish any of the aforementioned organisms as causative for clinical infection. A fourfold in- Table 2. Time Intervals Necessary for Preliminary Identification of Selected Opportunistic Organisms From Cultures of Tissue or Fluid Specimens Organism Interval Legionella spp. Nocardia asteroides Mycobacterium tuberculosis M. avium-intracellulare complex Aspergillus spp. Zygomycetes spp. Blastomyces dermatitidis* Coccidioides immitis* Cryptococcus neoformans Histoplasma capsulatum* Sporothrix schenckii* Chlamydia trachomatis* Cytomegalovirus 3 days to 1 days 5 days to 4 wk 2 to 8 wk 3 to 8 wk 1 to 5 days 1 day to 2 wk 4 days to 4 wk 3 days to 4 wk 4 days to 6 wk 5 days to 6 wk 4 days to 1 wk 2 to 3 days <24 hours with use of monoclonal antibody fluorescence technique l '' 7,98 5 days to 3 wk with use of conventional cell culture technique Rare opportunistic pathogen in immunosuppressed patients.

14 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 623 crease in IgG antibodies should be observed during convalescence. Fungal infections may manifest as strongly positive results of serology at the onset of clinical illness. Usually, an infection must be present for 2 to 4 weeks before serologic results are positive. The interpretation of titers of complement-fixation and latex-agglutination studies for fungi is shown in Table 21. The immunodiffusion test does not result in a titer; the results are either positive or negative. A "band of identity," which is observed on agar, indicates the presence of antibody to a particular fungus. Positive results of immunodiffusion tests are highly suggestive of an active infection from Aspergillus species, B. dermatitidis, or H. capsulatum. False-negative results of immunodiffusion tests occur frequently with ß. dermatitidis but less often with H. capsulatum and Aspergillus species. 199 Detection of cryptococcal antigen in the serum in the absence of rheumatoid factor (rheumatoid factor cross-reacts with the antibody used with the latex-agglutination test) likely implies active fungemia. Biopsy of Mucocutaneous Lesions. Lesions of the skin or mucous membranes in patients who have pulmonary can result from disseminated infection with a common organism. As discussed earlier, dissemination can occur with fungi, mycobacteria, and general bacteria (especially P. aeruginosa and rarely Legionella species), N. asteroides, Actinomyces species, and the herpes viruses (herpes simplex and herpes zoster). With any suspicious mucocutaneous lesion, a biopsy specimen should be obtained and processed with hematoxylin Table 21. Serologic Studies Currently Used at the Mayo Clinic (Organisms Associated With Infections in Immunocompromised Patients) Significant result Organism Test* Acute Convalescent Bacteria Legionella pneumophila (types l-iv) or micdadei Mycoplasma pneumoniae Viruses Cytomegalovirus Chlamydia trachomatis Toxoplasma gone/// Fungi Aspergillus fumigatus, flavus, or niger Blastomyces dermatitidis Coccidioides immitis Cryptococcus neoformans Histoplasma capsulatum Sporothrix schenckii Indirect immunofluorescence Complement fixation IgG anticomplement immunofluorescence IgM indirect immunofluorescence Complement fixation IgG indirect immunofluorescence IgM indirect i m m u nof I uorescence Immunodiffusion Complement fixation Immunodiffusion Complement fixation Latex agglutination (detection of antigen) Complement fixation Immunodiffusion Latex agglutination Serology detects IgG antibody unless otherwise specified. >1:256 Any 4-fold rise 2*1:16 Any 4-fold rise 3*1:16 Any 4-fold rise s»1:1 >1:64 Any 4-fold rise 5=1:1,24 Any 4-fold rise 3=1:8 One or more bands suggestive of active infection Titers of 1:8 or 1:16 suggestive of active infection; 1:32 highly suggestive of active infection Positive highly suggestive of active infection Titers of s= 1:2 suggestive of active infection Any positive active infection, although rheumatoid factor can produce false-positive results Titers of 1:8 or 1:16 suggestive of active infection; 3=1:32 highly suggestive of active infection M band alone early infection, late or treated infection, or after skin testing; H band and M band active infection Titers of 5=:8 usually, active infection

15 624 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 and eosin stain, acid-fast or auramine-rhodamine stain, Nocardia stain (modified Kinyoun stain), Gram stain, and methenamine silver stain; samples should also be cultured for aerobic and anaerobic bacteria, mycobacteria, fungi, and viruses. Besides infections, mucocutaneous lesions can be malignant infiltrations or a vasculitis such as Wegener's granulomatosis. The clinician should carefully analyze serologic data and the microbiologic and histopathologic information obtained from biopsy specimens of mucocutaneous lesions. Although a common agent may cause mucocutaneous lesions and pulmonary in immunocompromised patients, it may not be the sole etiologic factor responsible for the pulmonary involvement. Examination of Body Fluids and Secretions Other Than Pulmonary Secretions.- -Microbiologic processing (including stains, cultures, and, when appropriate, serologic studies) of body fluids other than pulmonary secretions for example, blood, pleural effusions, nasogastric aspirates, bone marrow aspirates, joint fluid, cerebrospinal fluid, and urine may contribute diagnostic information. Several blood cultures should be obtained in all patients, preferably at various time intervals. Some immunocompromised patients with pulmonary infectious disease may not have fever; nevertheless, blood cultures may be positive. Blood samples should be cultured for aerobic and anaerobic bacteria, mycobacteria, and fungi. New blood culturing techniques that provide a lysed centrifuged specimen of blood for culture may result in higher recovery rates of mycobacteria and fungi. 2,21 Patients with C. neoformans lung disease should have a cerebrospinal fluid examination to rule out infections of the central nervous system. In patients with pulmonary nocardiosis, computed tomography of the head should be considered to rule out occult cerebral abscesses. Other studies that may be helpful in diagnosing pulmonary in the ICH are examination of stool specimens for ova and parasites (in an effort to detect the nematode 5. stercoralis) and a differential leukocyte count (to disclose active leukemia or eosinophilia). Eosinophilia may be associated with acute lung injury (such as that caused by methotrexate), parasitic or fungal infection, or vasculitis. Increased uptake of gallium radionuclide in the lungs may indicate early cytotoxic lung injury or P. carinii pneumonia in febrile, dyspneic immunocompromised patients (for example, those with AIDS) with normal chest roentgenographic findings. 14,171,22 A thorough funduscopic examination, preferably by an ophthalmologist, may detect exudative lesions, which can be associated with disseminated fungal, cytomegalovirus, or Toxoplasma infections. Invasive Diagnostic Procedures. Transtracheal Needle Aspiration. Several comparative studies have shown that less oropharyngeal contamination occurs in sputum obtained by transtracheal needle aspiration than in an expectorated specimen. 23 " 26 With use of this method, culturing for anaerobic bacteria is possible. The frequency of occurrence of anaerobic bacterial pneumonia in the ICH, however, is probably low. In a recent review of 95 open-lung biopsy procedures in immunocompromised patients performed at our institution, no anaerobic infections were identified. 27 Transtracheal needle aspiration may be of value in the ICH with abscess cavities and a history compatible with anaerobic infection (for example, aspiration pneumonitis or anaerobic bacteremia). 28,29 When all microbes are considered, the yield and expedience of diagnosis by transtracheal needle aspiration parallel those of a spontaneous or induced sputum collection. Because we have encountered severe complications, especially prolonged hemorrhage, with use of transtracheal needle aspiration in thrombocytopenic patients, this procedure is not being used for such patients at our institution. Bronchoscopy. With use of bronchoscopy, in combination with transbronchial brush biopsy or forceps biopsy, direct inspection of bronchial and parenchymal lung tissue is possible. Consequently, not only infection but also cytotoxic lung effects, malignant infiltrations, and, rarely, vasculitis may be identified. Tissue invasion by molds (such as Aspergillus species or Zygomycetes) may also be seen. Generally, the diagnostic yield is greatest when diffuse pulmonary are present. Feldman and associates 21 reported a diagnostic yield of 84% in patients with diffuse pulmonary in comparison with 43% in patients with localized disease, all of whom underwent transbronchial biopsy. Several series have reported the efficacy of touch preparations of biopsy tissue for the detection of P. carinii pneumonitis. 211,212 Use of a modified bronchoscope with a special sterile sleeve allows aerobic and anaerobic culturing of bronchial secretions, presumably without oropharyngeal microbial contamination. 213 Despite all these factors, the bronchoscopist may be unable to obtain an adequate or appropriate sample of tissue. An ample amount of tissue is necessary for the variety of stains and cultures needed to rule out all causes (infectious and noninfectious) of pulmonary. Furthermore, peripheral or localized pulmonary may be difficult to reach by bronchoscopic biopsy techniques. One variable that is difficult to control is the approach of the bronchoscopist. What is the optimal number of biopsy specimens? From how many areas of the involved lung

16 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 625 should tissue be obtained? The varied techniques of bronchoscopists likely have an indeterminate effect on ultimate diagnostic yield. Bronchoalveolar lavage involves wedging of the bronchoscope into a diseased subsegment of lung tissue. The area is lavaged with approximately 2 ml of sterile isotonic saline, which is then aspirated. The aspirated fluid is then submitted to the laboratory for appropriate staining procedures and cultures. A recent study by Stover and associates 214 suggested that bronchoalveolar lavage is an effective technique for diagnosing diffuse pulmonary disease in the ICH who does not have AIDS. With use of this technique, 83% of opportunistic infections were diagnosed by those investigators; however, only 46% of cases of malignant infiltration and 4% of cases of drug toxicity were diagnosed. Two of 12 patients with cytomegalovirus did not have histologic confirmation of cytomegalovirus disease. If these two cases are excluded, the diagnostic yield for cytomegalovirus was 66%. Further studies are necessary to confirm the reliability of this technique as a diagnostic aid in the ICH. We reviewed all bronchoscopies (including those with and those without transbronchial biopsy) and all openlung biopsies performed on immunocompromised patients (none of whom had AIDS) at our institution from January 1978 through December 198. Of the 65 bronchoscopies performed, a specific etiologic diagnosis was determined immediately in only 4 (6%). Two patients had P. carinii infection diagnosed on toluidine blue stains of touch preparations, one patient had organisms that resembled C. neoformans on silver stain of a biopsy specimen, and one patient had organisms that resembled Rhizopus on silver stain of biopsy tissue. In eight additional patients (12%), a diagnosis was made within 24 hours. Although atypical mycobacteria and fungi (for example, M. avium-intracellulare complex, Candida, and Aspergillus species) were ultimately recovered from cultures of many of these bronchoscopic specimens, the clinician could not determine whether such organisms were true pathogens, were merely colonizing the respiratory tree, or were laboratory contaminants. Among 28 patients who underwent bronchoscopy (13 with transbronchial lung biopsy) of a total of 95 patients who later had open-lung biopsy, no diagnosis was made in 24 (86%). 27 Open-lung biopsy yielded a specific diagnosis in 19 of 24 (79%) of these patients. In the four remaining patients, the same diagnosis was made with use of bronchoscopy and with use of open-lung biopsy, although the results obtained from bronchoscopy were often delayed, incomplete, or of questionable validity. These findings agree with those of Toledo-Pereyra and associates, 215 who reported that only 1 of 2 (5%) transbronchial biopsies performed on immunocompromised patients during a 17-month period resulted in a specific diagnosis. Later, open-lung biopsy in 1 of 13 of these patients (77%) yielded a specific diagnosis. A comparison of reported series of invasive procedures (bronchoscopic biopsies, percutaneous biopsies, thoracoscopy-guided biopsies, and open-lung biopsies) for diagnosing pulmonary is shown in Table 22. This extensive tabulation includes only those series of invasive pulmonary procedures in immunosuppressed patients that clearly defined and distinguished acceptable specific etiologic diagnoses from nonspecific etiologic diagnoses. The reader is referred to other reports in which specific etiologic diagnoses were not clearly defined or were unacceptable on critical review. 23 " 233 In many cases, specific microbial agents implicated as pathogens may have been contaminants, or "specific" pathologic descriptions of tissue were, in fact, nonspecific for example, "viral pneumonitis." Bronchoscopic techniques are reliable for diagnosing P. carinii pneumonia in patients with AIDS. In this group of patients, the sensitivity of transbronchial biopsy for diagnosing P. carinii pneumonia is approximately 9% for transbronchoscopic fixed tissue and touch imprint biopsies, 4 to 5% for brush biopsies, and 8% for bronchoalveolar lavage. 191,234 Cytologie evaluation of fluid from bronchoalveolar lavage in the ICH without AIDS but with an extrapulmonary malignant lesion may identify neoplastic cells. 235 In this situation, however, the clinician must be cautious in attributing pulmonary exclusively to a malignant process. As discussed previously, other etiologic factors may be operant and lung tissue may be necessary for diagnosis. Transbronchial brush biopsy is associated with fewer complications than is transbronchial forceps biopsy. Nevertheless, in most reported series, the complication rates associated with both these procedures exceed that for open-lung biopsy (Table 22). 2 ' 6236 Hemostasis may be a problem in thrombocytopenic patients. Both techniques are, in effect, blind procedures because the tissue is obtained from an area that cannot be directly observed for hemorrhage. Pneumothorax may be a complication of either procedure. Percutaneous Needle Aspiration. Percutaneous needle aspiration (with use of fluoroscopic guidance and a thin-walled 18- to 2-gauge needle), if successful, yields fluid for microbiologic stains and cultures and cytology; no tissue is obtained. With percutaneous needle biopsy (for example, with use of a modified Vim- Silverman cutting needle), variable amounts of tissue are obtained. The disadvantages of both these procedures are the frequent complications (pneumothorax and hem-

17 626 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 Table 22. Comparison of Reported Series of Invasive Procedures for Diagnosing Pulmonary Infiltrates in Immunocompromised Patients Who Did Not Have Acquired Immunodeficiency Syndrome* Procedure Etiologic diagnosis (%) Complications (%) Author Type No. Comments Specific Nonspecific None Pneumothorax Hemorrhage Other Feldman TBBB et al 2 ' 11 Finley etal 2 ' 2 Cunningham et al 2 ' 6 Nishio and Lynch 2 ' 7 Aisner et al 2 ' 8 Matthay et al 2 ' 9 Jaffe and Maki' Chuang 22 Stover et al 214 Bandt et al 22 ' Costellino and Blank' 4 Zavala and Schoell 222 Jaffe and Maki' Cunningham et al 2 ' 6 Dijkman et al 223 Rodgers 224 Waltzer et al 225 Jaffe and Maki' Cockerill et al 27 Wolff et al 226 Singer etal 4 TBFB TBBB TBBB TBFB TBBB TBFB TBBB TBBB TBFB TBFB TBFB BAL 97 PC 25 PC 18 PC 11 PCTDB 5 PCTDB 17 TCB 28 TGB 42 OLB 23 OLB OLB OLB OLB ; all patients with lymphoma All diffuse Focal pulmonary All diffuse All diffuse interstitial ; all patients <18yrold ; all renal transplant recipients interstitial ; all children All diffuse pulmonary D D

18 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST 627 Author Prober et al 227 Toledo- Pereyra etal 2 ' 5 Springmeyer et al 228 Creenman etal 9 Rossiter etal" Leight and Michaelis 229 Procedure Type No. OLB TBFB TBBB OLB TBBB TBFB OLB PC PCNB OLB OLB OLB 46 2t 2t 13* 23t 23t Comments ; all children 1 J I 1 All diffuse j I in bone marrow transplant patients ; 7/83 patients (84%) immunosuppressed Table 22 Continued Etiologic diagnosis (%) Specific Nonspecific None D Complications (%) Pneumothorax Hemorrhage *BAL = bronchoalveolar lavage; D = does not apply; = not available; OLB = open-lung biopsy; PC = percutaneous needle aspiration; PCNB = percutaneous needle biopsy; PCTDB = percutaneous trephine air drill biopsy; TBBB = transbronchial brush biopsy; TBFB = transbronchial forceps biopsy; TGB = thoracoscopy-guided biopsy. tconcomitant procedures. *Done after TBFB and TBBB Other orrhage) and the limitation of sampling to peripheral lung tissue. In most series of percutaneous needle aspiration or biopsy, the complication rates exceed those reported for both bronchoscopic biopsy and open-lung biopsy procedures (Table 22). 216 ' 221 ' 222 ' Thoracoscopy-Guided Biopsy. Recently, some pulmonologists have advocated thoracoscopy-guided biopsy for diagnosing pulmonary in the ICH. A flexible endoscope (thoracoscope) is inserted between the parietal and visceral pleura, and biopsy specimens of parenchymal lung tissues are obtained after direct inspection reveals the areas of maximal pulmonary. The diagnostic rates in two reported series were 64% 223 and 1%. 224 Not unlike percutaneous procedures, thoracoscopy-guided biopsy can cause hemorrhage and Pneumothorax, although perhaps less frequently (Table 22). With use of this procedure, variable amounts of tissue are obtained and sampling of tissue is restricted to the periphery of the lung. 223,224 Theoretically, the procedure is limited to patients with diffuse or accessible peripheral. Qpen-Lung Biopsy. When the "diagnostic yields" of the various invasive pulmonary procedures are compared, the data presented in the numerous published series must be carefully scrutinized. Many authors define a "positive diagnosis" as any histologic diagnosis and not a specific etiologic diagnosis. In the seriously ill patient with pulmonary, a specific etiologic diagnosis (especially in regard to infection) is necessary so that appropriate therapy can be initiated. In several reported series of open-lung biopsy procedures in immunosuppressed patients, this procedure was thought to be superior for establishing a specific etiologic diagnosis and was associated with fewer complications than some of the less invasive techniques. 1 ' ' 226 ' 229 During a 3-year period Oanuary 1978 through December 198) at our institution, 95 immunocompromised patients with pulmonary underwent open-lung biopsy. A specific etiologic diagnosis was established in 77 (81 %) of these patients; 12(13%) had more than one diagnosis. In 36 of the 77 patients (47%) with a specific etiologic diagnosis, the diagnosis was made on the basis of frozen sections or stains within 3 hours after open-lung biopsy. In 35 patients (45%), the diagnosis was established within 24 hours. Of the 95 patients, 12 (13%) experienced complications (pneumothorax, hemorrhage, or empyema); no deaths were attributed to the procedure.

19 628 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol 6 At our institution, a limited thoracotomy is performed with the patient under general anesthesia, and a specimen (3 by 4 cm) is obtained from the affected lung tissue by using a cutting stapler. The procedure usually lasts approximately 3 minutes. A chest tube is inserted in the intrapleural space and usually removed within 36 hours postoperatively. The specimen obtained from open-lung biopsy is processed as follows. A portion of the tissue is sent to the surgical pathology laboratory, where a frozen section examination with hematoxylin-eosin stain is performed immediately. The fixed specimen is prepared with hematoxylin-eosin, methenamine-silver, Gram, auraminerhodamine, and other stains as indicated. The remainder of the tissue is sent immediately in a sterile container to the microbiology laboratory, where (1) impression smears of the tissue are produced on glass slides, fluorescent antibody testing is performed (for Legionella), and methenamine-silver staining is done (for P. carinii) and (2) part of the specimen is homogenized with a sterile mortar and pestle. Cultures are prepared for Legionella, aerobic and anaerobic bacteria, fungi, mycobacteria, Nocardia, viruses, and Chlamydia. The stains fluorescent antibody for Legionella, Gram for bacteria, potassium hydroxide for fungi, auramine-rhodamine for mycobacteria, and modified Kinyoun for Nocardia are usually interpreted within 3 hours after the time of arrival in the laboratory, and the results are reported by telephone to the physician in charge of the patient's care. A specific protocol for the processing of lung tissue, as described, is essential to ensure that the proper tests will be done. A team approach is highly beneficial in caring for these patients. A concerted effort involving the primary physician, pulmonologist, infectious disease specialist, surgeon, microbiologist, and pathologist will likely provide the best directives for diagnosing the condition and treating the patients. At this time, open-lung biopsy seems to be the safest and most expeditious means for obtaining a diagnosis in most immunocompromised patients with pulmonary disease; however, further experience may show bronchoalveolar lavage to be of substantial value. Ideally, comparison studies of various diagnostic techniques should be conducted with homogeneous groups of patients. In many reported series (including our own), numerous patients with varied types of underlying diseases and varied types of pulmonary have been studied. At our institution, the cost of open-lung biopsy is about a third that of an intensive empiric trial of multiple antimicrobial agents (Table 19). The cost of bronchoscopy is about half that of open-lung biopsy. During our review of bronchoscopy and open-lung biopsy (1978 through 198), bronchoalveolar lavage was not performed. Because our diagnostic yield for bronchoscopy was low, this procedure, as performed in our institution, was obviously not cost-effective. This factor is an important consideration as cost-containment becomes increasingly emphasized in contemporary medical practice. In our series, the therapeutic management was altered in 89 of 95 patients (94%) after the results of open-lung biopsy were known. (Most of the therapeutic alterations involved the addition or elimination of an antimicrobial agent.) Our findings correspond to results in other reported series (Table 22) that is, open-lung biopsy has a high diagnostic specificity and low complication rate when compared with other conventional invasive procedures used for diagnosis of pulmonary in immunocompromised patients who do not have AIDS. Further confirmatory studies are needed, however, to assess the diagnostic capability of bronchoalveolar lavage in these patients. REFERENCES 142. Rubin RH: Systemic mycotic infections. In Scientific American Medicine. Section 7, Subsection IX. Edited by E Rubenstein, DD Federman. New York, Scientific American, 1978, pp Millar JW, Hörne NW: Tuberculosis in immunosuppressed patients. Lancet 1: , Kaplan MH, Armstrong D, Rosen P: Tuberculosis complicating heoplastic disease: a review of 21 cases. Cancer 33:85-858, Feld R, Bodey GP, Croschel D: Mycobacteriosis in patients with malignant disease. Arch Intern Med 136:67-7, Rubin RH, Greene R: Etiology and management of the compromised patient with fever and pulmonary. In Clinical Approach to Infection in the Compromised Host. Edited by RH Rubin, LS Young. New York, Plenum Medical Book Company, 1981, pp Siegel SE, Lunde MN, Gelderman AH, Halterman RH, Brown JA, Levine AS, Graw RG Jr: Transmission of toxoplasmosis by leukocyte transfusion. Blood 37: , Bock BV, Kirby BD, Edelstein PH, George WL, Snyder KM, Owens ML, Hatayama CM, Haley CE, Lewis RP, Meyer RD, Finegold SM: Legionnaires' disease in renal-transplant recipients. Lancet 1:41-413, Myerowitz RL, Pasculle AW, DowlingJN, Pazin GJ, PuerzerM, Yee RB, Rinaldo CR Jr, Hakala TR: Opportunistic lung infection due to "Pittsburgh pneumonia agent." N Engl J Med 31: , Rubin RH: Infection in the renal transplant patient. In Clinical Approach to Infection in the Compromised Host. Edited by RH Rubin, LS Young. New York, Plenum Medical Book Company, 1981, pp Masur H, Cheigh JS, Stubenbord WT: Infection following renal transplantation: a changing pattern. Rev Infect Dis 4: , Rubin RH, Wolfson JS, Cosimi AB, Tolkoff-Rubin NE: Infection in the renal transplant recipient. Am J Med 7:45-411, Burgos-Calderon R, Pankey GA, FigueroaJE: Infection in kidney transplantation. Surgery 7:334-34, Moore TC, Hume DM: The period and nature of hazard in clinical renal transplantation. 1. 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20 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Schweizer RT, Kountz SL, Beizer FO: Wound complications in recipients of renal transplants. Ann Surg 177:58-62, Naraqi S, Jackson GG, Jonasson O, Yamashiroya HM: Prospective study of prevalence, incidence, and source of herpesvirus infections in patients with renal allografts. J Infect Dis 136:531-54, FialaM, Payne JE, Berne TV, Moore TC, HenleW, Montgomerie JZ, Chatterjee SN, G.uze LB: Epidemiology of cytomegalovirus infection after transplantation and immunosuppression. J Infect Dis 132: , Peterson PK, Balfour HH Jr, Marker SC, Fryd DS, Howard RJ, Simmons RL: Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine (Baltimore) 59:283-3, Suwansirikul S, RaoN, DowlingJN, HoM: Primary and secondary cytomegalovirus infection: clinical manifestations after renal transplantation. Arch Intern Med 137: , Rubin RH, Russell PS, Levin M, Cohen C: Summary of a workshop on cytomegalovirus infections during organ transplantation. J Infect Dis 139: , Ho M, Suwansirikul S, Dowling JN, Youngblood LA, Armstrong JA: The transplanted kidney as a source of cytomegalovirus infection. N Engl J Med 293: , Rubin RH, Cosimi AB, Tolkoff-Rubin NE, Russell PS, Hirsch MS: Infectious disease syndromes attributable to cytomegalovirus and their significance among renal transplant recipients. Transplantation 24: , Simmons RL, Matas AJ, Rattazzi LC, Balfour HH Jr, Howard RJ, Najarian )S: Clinical characteristics of the lethal cytomegalovirus infection following renal transplantation. Surgery 82: , Myerowitz RL, Stalder H, Oxman MN, Levin MJ, Moore M, Leith JD, Gantz NM, Pellegrini J, Hierholzer JC: Fatal disseminated adenovirus infection in a renal transplant recipient. Am J Med 59: , Keller EW, Rubin RH, Black PH, Hirsch MS, Hierholzer JC: Isolation of adenovirus type 34 from a renal transplant recipient with interstitial pneumonia. Transplantation 23: , Meyers JD, Thomas ED: Infection complicating bone marrow transplantation. In Clinical Approach to Infection in the Compromised Host. Edited by RH Rubin, LS Young. New York, Plenum Medical Book Company, 1981, pp Neiman P, Wasserman PB, Wentworth BB, Kao GF, Lerner KG, Storb R, Buckner CD, Clift RA, Fefer A, Fass L, Glucksberg H, Thomas ED: Interstitial pneumonia and cytomegalovirus infection as complications of human marrow transplantation. Transplantation 15: , Meyers JD, Spencer HC Jr, Watts JC, Gregg MB, Stewart JA, Troupin RH, Thomas ED: Cytomegalovirus pneumonia after human marrow transplantation. Ann Intern Med 82: , Beschorner WE, Hutchins GM, Burns WH, Saral R, Tutschka PJ, Santos GW: Cytomegalovirus pneumonia in bone marrow transplant recipients: miliary and diffuse patterns. 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21 63 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Mayo Clin Proc, September 1985, Vol Blumenfeld W, Wagar E, Hadley K: Use of the transbronchial biopsy for diagnosis of opportunistic pulmonary infections in acquired immunodeficiency syndrome (AIDS). Am J Clin Pathol 81:1-5, Coleman DL, Dodek PM, Luce JM, Golden JA, Gold WM, Murray IF: Diagnostic utility of fiberoptic bronchoscopy in patients with Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome. Am Rev Respir Dis 128: , Goodman JL, Tashkin DP: Pneumocystis with normal chest x-ray film and arterial oxygen tension: early diagnosis in a patient with the acquired immune deficiency syndrome. Arch Intern Med 143: , Gordin FM, Simon GL, Wofsy CB, Mills ): Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1: , Kovacs JA, Hiemenz JW, Macher AM, Stover D, Murray HW, ShelhamerJ, Lane HC, UrmacherC, Honig C, Longo DL, Parker MM, Natanson C, Parrillo JE, Fauci AS, Pizzo PA, Masur H: Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1: , Murray PR, Washington JA II: Microscopic and bacteriologic analysis of expectorated sputum. Mayo Clin Proc 5: , Zuravleff JJ, Yu VL, Shonnard JW, Davis BK, Rihs JD: Diagnosis of Legionnaires' disease: an update of laboratory methods with new emphasis on isolation by culture. JAMA 25: , GleavesCA, Smith TF, Shuster EA, Pearson GR: Rapid detection of cytomegalovirus in MRC-5 cells inoculated with urine specimens by using low-speed centrifugation and monoclonal antibody to an early antigen. 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22 Mayo Clin Proc, September 1985, Vol 6 PULMORY DISEASE IN THE IMMUNOCOMPROMISED HOST Lauver GL, Hasan FM, Morgan RB, Campbell SC: The usefulness of fiberoptic bronchoscopy in evaluating new pulmonary lesions in the compromised host. Am J Med 66:58-585, 1979 Satterfield JR Jr, McLaughlin )S: Open lung biopsy in diagnosing pulmonary in immunosuppressed patients. Ann Thorac Surg 28: , 1979 Hedemark LL, Kronenberg RS, Rasp FL, Simmons RL, Peterson PK: The value of bronchoscopy in establishing the etiology of pneumonia in renal transplant recipients. Am Rev Respir Dis 126: , 1982 Murray JF, Felton CP, Garay SM, Gottlieb MS, Hopewell PC, Stover DE, Teirstein AS: Pulmonary complications of the acquired immunodeficiency syndrome. N Engl ) Med 31: , Young JA, Hopkin JM, Cuthbertson WP: Pulmonary in immunocompromised patients: diagnosis by cytological examination of bronchoalveolar lavage fluid. J Clin Pathol 37:39-397, Andersen HA, Fontana RS, Sanderson DR, Harrison EG jr: Transbronchoscopic lung biopsy in diffuse pulmonary disease: results in 3 cases. Med Clin North Am 54: , Fontana RS, Miller WE, BeaboutJW, Payne WS, Harrison EGJr: Transthoracic needle aspiration of discrete pulmonary lesions: experience in 1 cases. Med Clin North Am 54: ,197 ttaiwlnij THAiuN» : fjm\ 9.5 ί Founder of Modern Thai Medical Education Rungson Sittipong, M.D., Marc A. Shampo, Ph.D., and Robert A. Kyle, M.D. Prince Mahidol of Songkhla, one of the founders of modern medical education in Thailand, received his medical degree with honors from Harvard University in He was the father of the present king of Thailand, King Bhumibol, and a grandson of King Mongkut of The King and I fame. Born in 1892, Prince Mahidol left Thailand when he was 12 years old to study in England. He later took a course in naval science in Germany, and during World War I, he returned to Thailand to serve in the Royal Navy. In 1916, however, 24-year-old Mahidol sailed for the United States and enrolled in the medical program at Harvard University. In his third year of the public health program (after completing 2 years of medical studies), he returned to Thailand because of the death of his mother. While in Bangkok, the prince worked in the laboratory of the Siriraj Hospital, and he donated funds for educational grants to medical students and for construction of medical school buildings and patients' wards. Returning to the United States at the end of 192, Mahidol continued his public health studies at Harvard and the Massachusetts Institute of Technology, and in June 1921, he received a certificate in public health from Harvard. On his way home, the prince met in Europe with representatives of the Rockefeller Foundation and persuaded them to provide medical and public health aid to Thailand the beginning of American assistance for Thailand's medical development. Inaugurated on Oct. 1, 1923, this aid was especially helpful in the areas of medicine, nursing, and public health. Arriving in Thailand at the end of November 1923, Prince Mahidol began his educational endeavors, teaching the Faculty of Medicine, Faculty of Liberal Arts, and Faculty of Sciences of Chulalongkorn University. In 1924, he dedicated the McCormick Hospital of the American Presbyterian Mission in Chiang Mai, a province in northwestern Thailand. Prince Mahidol worked so devotedly that his health became impaired, and he was advised to take a rest abroad. Mahidol again sailed to the United States not to rest, but to finish his medical studies at Harvard. After receiving his medical degree and recovering from a renal problem and an appendectomy, he returned to Thailand in December He worked at the McCormick Hospital in Chiang Mai but became ill and returned to Bangkok, where he died on Sept. 24, Both of Prince Mahidol's sons became kings of Thailand: Prince Ananda Mahidol ascended to the throne in 1934, and on his death in 1946, his American-born brother, Prince Bhumibol Adulyadej, became the ninth ruler of the Chakkri dynasty. A stamp was issued by Thailand in 1983 to commemorate the 6th anniversary of the cooperation between the Faculty of Medicine now of Mahidol University and the Rockefeller Foundation and to honor the memory of Prince Mahidol of Songkhla, whose royal portrait appears on the stamp.