Infectious Disease Problems in Various Hematologic Disorders

Symposium on Clinical Signs

of Blood Disease

Infectious Disease Problems in Various Hematologic Disorders Leon G. Smith, M.D.* and Donald Louria, M.D.**

Various hematologic disorders can affect the quantity and quality of granulocytes and lymphocytes. The white blood cell dysfunction can be either congenital or acquired. The host defends itself against certain microbiologic pathogens by granulocytic activities, and others primarily by humoral or lymphocytic cellular mechanisms. The granulocyte is one of the body's primary means of defense against an invading organism. Metchnikoff recognized this in 1882 and called these cells "phagocytes."7 These cells have two major functions: to engulf the organism with the help of opsonins and to destroy the pathogen within the granulocyte. Thus, a quantitative deficiency of such cells, as with aplastic anemia or acute leukemia, or a specific defect in the granulocyte, as with the lysosomal or other intracellular abnormalities, results in diminished phagocytosis and killing activity against many common organisms, such as S. aureus, pneumococci, streptococci, and E. coli. Such intracellular defects are noted in hereditary myeloperoxidase deficiency disease, glucose-6-phosphate dehydrogenase white cell deficiency, and Chediak-Higashi Disease. Granulocytic abnormalities and the pathogens which tend to invade hosts with such deficiencies are listed in Table 1. We shall illustrate the more common infectious disease problems in the various host deficient states. Our comments will be centered on diagnostic possibilities and therapeutic necessities as various problems present.

GRANULOCYTE ABNORMALITIES DECREASED NUMBER OF GRANULOCYTES

A 22 year old white woman enjoyed good health until 1 day prior to admission to the hospital, when she developed a shaking chill with a high *Director, Department of Medicine, Saint Michae!'s Medical Center, Newark, New Jersey "*Professor and Chairman, Department of Preventive Medicine, New Jersey College of Medicine, Newark, New Jersey

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Table 1. Relationship of Underlying Disease to Certain Superinfecting Microorganisms GRANULOCYTIC ABNORMALITIES

Acquired Acute myelogenous leukemia ) Aplastic anemia Acute lymphoblastic leukemia Drug-induced leukopenia Myeloperoxidase deficiency Acute granulocytic leukemia (feW)} Refractory megaloblastic anemia Congenital or Hereditary Chronic granulomatous disease, } Lipochrome histocytosis

PATHOGENS CAUSING SUPERINFECTION

Pseudomonas sp. Enterobacter sp. S. aureus D. pneumoniae Clostridium sp.

1

Candida { ? S. aureus ? E. coli

I

Catalase-containing bacteria including: S. aureus Serratia Marcescens Salmonella sp. E. coli, Klebsiella sp.

Glucose-6-phosphate dehydrogenase deficiency Chediak-Higashi disease

Various bacterial Various bacterial (particularly S. aureus)

Primary myeloperoxidase deficiency

Candida

fever. On admission, her temperature was 104 F; blood pressure was 128 mm. Hg systolic, 80 diastolic; pulse 100, and respirations 18. Examination revealed a toxic, well oriented white woman with ecchymoses of the extremities and the lower portion of the trunk. There was a fresh hemorrhage in the right eye. The peripheral white cell count was 64,000 cells per cu. mm. On peripheral smear, the predominant cells were blasts. The platelet count was 15,000 per cu. mm. The chest x-ray was negative. (Blood cultures were taken.) Steroids and antibiotics were begun for the leukemia and presumptive bacteremia. It is impossible to determine at this point whether this illness is due to the disease itself (50 per cent chance) or due to an invading organism.1 The organisms most likely to be implicated are S. aureus, D. pneumoniae, Streptococcus pyogenes, and strains of enterobacter or pseudomonas. 1 A small pustular skin lesion with a red base may point to a gramnegative organism. Bullae or erythematous skin lesions lead one to think of a gram-positive organism. Acute infiltration of the lung would be found more frequently with the pneumococcus or S. aureus, but pseudomonas may produce the same effect on occasion. In summary, there is no definite means of detecting which pathogen is at work in this leukemic person. Withholding therapy would be disastrous. Thus, one must treat on a statistical basis with broad antibiotic therapy. Orders for this patient read as follows: 0

1. Draw 3 sets of blood culture samples 15 minutes apart after using an iodine preparation of the skin. 2. Begin therapy after cultures are complete.

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3. Cephalothin, 2 gm. intravenously in rapid drip over a 20 min. period, every 4 hours. 4. Gentamicin, 5 mg. per kg. per day intramuscularly in divided doses every 8 hours for 3 days, then reduce to 3 mg. per kg. per day. 5. Carbenicillin 2 gm. intravenously every 2 hours in rapid drip. Do not mix any of the antibiotics. 6. Draw blood for later serologic tests if needed.

This patient indeed had a pseudomonas bacteremia; she responded to therapy, went into remission as well. All attempts should be made to place the leukemia in remission with proper drug treatment. Furthermore, repeat culture may reveal the pathogen during the therapeutic antibiotic trial. This type of reasoning is also applicable to patients with acute lymphocytic leukemia for the granulocyte is often eliminated by the invasion of the bone marrow by these malignant cells. Lymphosarcoma, aplastic anemia (whatever the cause), and various chemotherapeutic regimens that affect numbers of granulocyte numbers should be handled in like manner. Another pathogen that may invade in these granulopenic patients is clostridium. The clostridium infection can occur with or without gas formation. To illustrate this complication let us consider a 39 year old white man with severe granulocytopenia with acute myelogenous leukemia, who rapidly became septic. Later, he developed abdominal distention. Twenty-four hours later a fulminant cellulitis developed in the anal area, extending up the lower abdomen. Muscle pain and profound hypotension, hallmarks of this later stage, developed terminally. The orders for this patient were as follows: 1. Gram smear and culture of lesions aerobic and anaerobic. 2. Blood cultures, aerobic and anaerobic. 3. Begin 10 million units of aqueous penicillin every 6 hours intravenously to run "piggy-back" in 15 min. 4. Contact surgeon to remove necrotic area and open up tissue widely. 5. Place in hyperbaric oxygen chamber.

Despite early recognition and rapid treatment of this type of illness, the mortality approaches 100 per cent} Intestinal surgery or bowel manipulation in a leukopenic state predisposes to this clostridial invasion. SPECIFIC GRANlJLOCYTE DEFECTS

M yeloperoxidase Deficiency Myeloperoxidase deficiency of granulocytes delays intraleukocyte killing of certain bacteria,"especially candida, after these organsims have been phagocytized. S. aureus, C. tropicalis, and C. albicans, but not Strept. faecalis, are killed by myeloperoxidase. This phenomenon was studied by Rosenthal. 10 Lehrer and CHne" described a patient with chronic disseminated moniliasis who had hereditary myeloperoxidase deficiency. This deficiency occurs in some patients with acute myelogenous monocytic leukemia, but is not found ordinarily.5 One patient with a myeloproliferative disease and refractory megaloblastic anemia died of disseminated aspergillosis. 10

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The role of myeloperoxidase deficiency in acute granulocytic leukemia is being investigated thoroughly. The relationship of this disease to specific pathogenesis is interesting, but more data will be needed before we can relate this deficiency to susceptibility other than to candida.

Chronic Granulomatous Disease of Childhood This hereditary entity and a similar disease, lipochrome histocytosis, are characterized by recurrent infections, especially of the skin and bones, from infancy to the teenage period, eventually causing death. This disease is illustrated in an 8 year old boy, who presented with repeated bouts of septic arthritis of the knees. There was no predisposing trauma. Serratia marcescens was cultured from the red, swollen knee. The young boy had a history of repeated skin infections, especially of the neck, which required repeated surgical procedures. On microscopic section the organized abscess showed granuloma formation and hence the name of the disease. Granulocyte staining with N.B.T. (nitroblue tetrazolium) revealed a deficiency of dehydrogenase activity. The patient had previous infections of S. aureus, E. coli, salmonella species, but died ultimately of disseminated Serratia infection, despite adequate gentamicin therapy. Patients with chronic granulomatous disease have a defect in the ability of granulocytes to kill catalase-producing bacteria. 8 Hydrogen peroxide is required by the antimicrobial system of granulocytes of patients with chronic granulomatous disease. These organisms, such as S. aureus, with catalase activity, prevent the accumulation of the peroxide and thus prevent the destruction of the bacteria. This system, interestingly, is mediated by myeloperoxidase. This disease should be suspected in children with repeated skin, joint, or bone infections. It is confirmed by biopsy and special staining of the leukocytes. Despite appropriate antibiotic therapy, the oldest surviving patient of this disease is 19 years old. Chediak-Higashi Disease Chediak-Higashi disease is another interesting hereditary (autosomal recessive) entity characterized by repeated infection which can be attributed to a defective granulocyte. Children with Chediak-Higashi disease die within the first few years of life. We have seen a 2 year old white girl with eczema and mental deficiency who suffered with repeated skin and respiratory infections caused by various pathogens. She succumbed to a S. aureus pneumonia despite massive methicillin therapy. The granulocytes characteristically had the dark granules seen in the peripheral smears of these patients. These granules are considered to be giant lysosomes. There are at least four abnormalities in Chediak-Higashi disease: 17 (1) a defect in chemotaxis; (2) a delay in killing of phagocytized bacteria; (3) abnormallysosomes; (4) a decrease in circulating granulocytes. At present there is no good therapy for these patients. Prophylactic use of antibiotics has not been effective. S. aureus and, occasionally, streptococci or H. infiuenzae are the prime pathogens causing the characteristic skin abscesses and respiratory tract infection, respectively.4

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IMMUNE DEFICIENCY DISEASES INHERITED B-CELL DEFICIENCY DISORDERS

Although there is one type of granulocyte, there are two very distinctly different lymphocytes. The B cells (or Bursa cells) are large lymphocytes that produce the immunoglobulins A, G, and M. These cells are produced in the lymph nodes in contradistinction to T cell lymphocytes, which are derived from the thymus. The T cell is responsible for cellular immunity as illustrated by the tuberculin reaction rather than humoral or circulating immunoglobulins. As listed in Table 2, the B and T cell deficiencies can be congenital, hereditary, or acquired. The type of invading pathogen differs markedly, depending on whether the cellular or humoral system is disrupted. Usually Band T cell deficiency diseases are partial rather than total except for B cells of Bruton's disease and T cells of DiGeorge's syndrome. Bruton's Disease The hereditary B cell deficiency state is best illustrated by a 6 year old boy who had had 6 bouts of pneumonia beginning at age 1. His sweat tests were normal. He had no detectable immunoglobulins by immunodiffusion techniques. Like most of these patients he had numerous pulmonary and skin infections with the pneumococcus and S. aureus accounting for most of his problem. Bronchiectasis later developed despite adequate replacement of gammaglobulin monthly and prophylactic oxacillin antibiotic against the pneumococcus and S. aureus. Patients suffering from this male sex-linked disease are characteristically susceptible to pneumococcal or staphylococcal infections. Respiratory tract, bone, and joint infections are particular problems. Bruton's type of agammaglobulinemia is also associated with H. influenzae, meningococcal, and on rare occasion Pneumocystis carinii invasion of the lung. 6 , 11 Susceptibility to bacterial pathogens can be reduced by administering gamma globulin at monthly intervals. The Swiss-Type of Hypogammaglobulinemia This disorder may be associated with various supervening infections, including those caused by bacterial pathogens, pneumocystis, carinii species, and numerous viral agents. 6 In these cases there appears to be a genetic factor which inhibits stem cells from developing into lymphoid cells, resulting in the absence of an immunoglobulin-producing system. The disease can be recognized in infants by the severe deficiency of circulating lymphocytes and recurrent infections, especially severe and prolonged oral thrush. The Swiss type hypogammaglobulinemia appears to be a simple autosomal recessive transmission disease whereas Gitlin's disease, a closely related entity, is a sex-linked recessive disease. Despite the administration of amphotericin B for the monilia and pentamidine for the difficult to diagnose pneumocystis infection, the outcome is bleak, death ordinarily occurring within the first 8 days of life. 6

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Table 2. Relationship of Underlying Disease to Certain Superinfecting Microorganisms PATHOGENS

LYMPHOCYTIC DEFICIENCY DISEASE

Congenital Humoral -B cell deficient Bruton type hypogammaglobulinemia

Group A streptococcus D. pneumoniae Hemophilus influenza Meningococcus S. aureus Pneumocystis carinii Pseudomonas sp.

Combined Band T cell deficiency Swiss type agammaglobulinemia

Various bacterial Candida Pneumocystis carinii Viral D. pneumoniae Sinopulmonary pathogens S. aureus H. influenzae

Ataxia telangiectasia (lA deficiency)

Cellular T cell deficiency Di George syndrome} N ezelof disease

{

Candida Viral

Acquired B Cell deficiency Myeloma (mild T cell deficiency aISO))jD pneumoniae Heavy chain disease S. aureus Macroglobulinemia E. coli Benign follicular lymphoma H zoster Affecting B or T cells or both Chronic lymphatic leukemia Band T cells susceptible pathogens T cell deficiency state Hodgkin's disease, lymphoma Mycobacterium tuberculosis Cryptococcus; cytomegalovirus Cytomegalic virus Nocardia Listeria Brucella sp. Virus of multifocalleukoencephalopathy Vaccinia H. zoster Mucor mycosis Aspergillosis Sarcoid Mycobacterium tuberculosis Cryptococcus

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Ataxia Telangiectasia This is another interesting disease in which IgM and IgG are usually normal. IgA levels are low in half of the cases. The thymus eT cell) is embryonic and the B cells are partially deficient. These patients suffer repeated sinopulmonary infections, especially with D. pneumoniae, S. aureus, and H. influenzae; these can usually be managed by standard treatment with appropriate antibiotics and proper pulmonary drainage. 6 The T cell deficiency can be demonstrated by skin testing and by inadequate rejection of skin grafts, but appears to produce no predisposition to superinfection related to T cell abnormalities in these patients. However, the neurologic defects are progressive, ordinarily resulting in death between 4 and 12 years of age.

ACQUIRED B-CELL DEFICIENCY DISORDERS

The acquired humoral immunoglobulin deficiency states are seen most often in multiple myeloma, heavy chain disease, macroglobulinemia, and chronic lymphatic leukemia. The increased susceptibility to bacterial infections, particularly pneumococcal pneumonia, may precede the other clinical manifestations of myeloma. In all of these conditions there may be a decrease in concentration of normal immunoglobulins. The defect appears to be a problem of synthesis rather than increase catabolism or loss.14 A 50 year old white physician was admitted to Saint Michael's Medical Center with fever and coma of several hours' duration. Six months prior to admission, the patient had had similar symptoms and the disorder was diagnosed as acute purulent meningitis caused by D. pneumoniae. No anatomic or hematologic defect was present. The protein electrophorectic pattern was normal. He responded to penicillin therapy. One day prior to admission the patient developed fever and a severe headache. He gradually became more obtunded and became comatose an hour before admission. On physical examination, his temperature was 103 F. He was critically ill with profund coma and myoclonic twitching. His neck was stiff. No Babinski or abnormal reflexes were present. Abnormal laboratory findings included a white cell count of 30,000 per cu. mm. with a marked shift to the left, a hematocrit of 32, and a 2+ proteinuria. The cerebrospinal fluid had 800 polymorphonuclear leukocytes per ml., 22 mg. sugar and a 96 mg. protein per 100 ml. The protein electrophoretic pattern showed a prominent spike in the gamma globulin portion. Bence-Jones protein was found in the urine. On 24 million units of penicillin, the patient gradually recovered over a 2 week period. At the time of discharge, his memory for recent events was still poor. Presumably, the susceptibility to pneumococcal infection results from defective formation of opsonizing antibody. Patients with myeloma are not inadvertently susceptible to most viral infections but do acquire zoster infections. The frequency of herpes zoster infections rivals that observed in Hodgkin's disease, suggesting that some patients may have a 0

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T cell deficiency as well. Pneumonia is the primary manifestation. Meningitis is a rarer manifestation. S. aureus and E. coli are less common pathogens. Those suffering from heavy chain disease often succumb to the bacterial pathogens associated with B cell deficiencies.

Chronic Lymphatic Leukemia Patients with chronic lymphatic leukemia may demonstrate a B or T cell deficiency or both. Fifty per cent of these patients develop severe hypogammaglobulinemia, and are consequently (eventually) susceptible to pneumonia caused by a variety of bacterial pathogens. Recently, a patient with chronic lymphatic leukemia had six bouts of pneumococcal pneumonia despite administration of gamma globulin. Late in the course of the patient's illness, following a problem with hemolytic anemia where a short course of steroids was needed, unremitting fever developed, lasting 4 weeks. All blood cultures, spinal fluid examination, and numerous chest x-rays were normal. Subsequently, there was a 4-fold rise in the cytomegalic virus titer. At no time was the patient toxic and most of the medical staff were prepared to attribute the fever to the leukemia itself, which is very rarely a cause of fever in this form of leukemia. The only clues that lead to the diagnosis were the basic illness and the nontoxic state. The patient's fever disappeared spontaneously with the fall in the cytomegalic virus titer. A persistent right lower lung lesion without fever then developed. Sputum cultures for routine bacteria, tubercule bacillus, and fungi were negative. The tuberculin skin tests (including second strength) were negative. Mumps, monilia, and trichophyton skin tests were also negative, attesting to the anergic state. The serum cryptococcal antibody levels were elevated and serum cryptococcal antigen was detectable. A subsequent biopsy of the lung revealed cryptococcus. Again, the right setting and no fever despite a prominent pulmonary picture suggests cryptococcus. Amphotericin B was effective in eliminating the cryptococcus. The following year, the patient developed high fever, toxic state and a left upper lobe infiltrate with negative sputum cultures and smears. This episode was due to Nocardia as demonstrated at autopsy. Nocardial pulmonary infiltrates tend to produce fever and toxemia. The special acidfast stains of the sputum, as well as the cultures, often are negative. Only after repeated tracheal aspiration, and occasionally after lung biopsy, is the diagnosis made. Most often the Nocardial infection is mistaken for tuberculosis because of its similar lung location. Long-term sulfa treatment still remains the treatment of choice for Nocardia even though penicillin and tetracycline may also be effective. The Nocardial infection may also present as only skin nodules or as a brain abscess. Usually there is an underlying disease, especially in T cell-deficient states, as in Hodgkin's disease. Patients with chronic lymphatic leukemia are usually predisposed to B cell pathogens. With therapy and a prolonged debilitated state, the T cell type of pathogen occasionally occurs late in the course of the illness.

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T -CELL

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DEFICIENCY DISORDERS

Acquired isolated T cell deficiency states occur in Hodgkin's disease, lymphomas, chronic lymphatic leukemia, and sarcoidosis. In such patients, there is skin anergy, but the humoral (gammaglobulin) system is unimpaired. The most frequent invading organisms are C. neoformans, M. tuberculosis, L. monocytogenes and N. asteroides. Hodgkin's Disease Hodgkin's disease best illustrates the types of pathogens seen in this group of T cell-deficient patients. Cryptococcal meningitis is often associated with few clinical manifestations. Headaches, visual defects, and mild sensorium abnormalities are common symptoms. The neck is usually supple and the cerebrospinal fluid shows lymphocytic pleocytosis. Spinal fluid antigen and antibody for cryptococcus is a new test which has merit. An india ink smear of the cerebrospinal fluid must be done, but is of diagnostic value in only 25 per cent of cases. Repeated culture in solid media using a large volume of cerebrospinal fluid is often helpful in finding the cryptococcus. Equally helpful are serologic tests and antibodies. C. neoformans is present in serum and Cryptococcal antigen is present in the cerebrospinal fluid in over 90 per cent of cases. 17 With Listeria, the picture is slightly different. Fever is usually, but not always, present and the neck is often stiff. The cerebrospinal fluid shows a predominance of either neutrophils or lymphocytes, the total cell count ranging up to 2000 cells per cu. mm. There may be a few red cells, and rarely the spinal fluid is bloody. The sugar and protein values are variable in Listeris infections of the central nervous system, but in cultures, L. monocytogenes is sometimes mistaken as a diphtheroid contaminant. In actuality, any diphtheroid isolated in culture that is hemolytic on blood agar should be considered to be L. monocytogenes. Recent data suggests that ampicillin is the agent of choice but L. monocytogenes infections can also be treated with high doses of penicillin or with combinations of erythromycin and tetracycline. 1 Nocardia causes many different clinical problems in patients with T cell abnormalities. 1 Often it is confused with tuberculosis, for nocardia produces lung pathology almost identical to that produced by M. tuberculosis. Affected individuals are toxic. The involvement may appear miliary, but most often is localized. Unlike tuberculosis, the lesions are less likely to be in the upper lobe. Special modified stains of the sputum can usually distinguish this acid-fast organism from M. tuberculosis. Culture on blood agar on Saboraud's media usually require a minimum of 2 weeks at 37° C. Excavation with abscess formation is an infrequent x-ray finding. Brain abscesses and skin nodular lesions are less common manifestations of N. asteroides. Sulfa drugs still produce the most desirable results if given for several months. These disease states also appear to be unusually likely to be complicated by progressive multifocalleukoencephalopathy, a rare disease of the central nervous system occurring in elderly patients with usually protracted lymphomas or leukemias. 2 The findings are bilateral but asymmetric nerve deficits, particularly of the second cranial nerve. 3 Headaches

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are reported frequently but the cerebrospinal fluid is ordinarily normal. The presence of characteristic inclusion bodies in the brain cells confirms the diagnosis. The agent causing multifocalleukoencephalopathy has been isolated and tentatively identified as a papova-like virus, related to S.V.40Y· 15 Tuberculosis, both pulmonary and extrapulmonary, occurs in approximately 5 per cent of patients with Hodgkin's disease and less so in patients with chronic lymphatic leukemia and other acquired T cell deficiencies.! Tuberculosis must be considered whenever an unexplained pulmonary infiltrate, a meningitis with lymphocytic predominance, or an unexplained fever is present. Since the skin test for tuberculosis is not of value in T cell-deficient patients, diagnosis must naturally be established by sputum (acid-fast) smears and cultures or by biopsy of a lymph node or the liver.

Il':HERITED

T -CELL

DEFICIENCY DISORDERS

There are two known diseases with congenital T cell deficiency states, the DiGeorge syndrome and Nazelof disease. Children with these disorders die within the first few months of infancy from virus and mucocutaneous candida infections. 6 The B cell system remains intact and pyogenic bacteria cause no particular problem. There remain two special problems that merit special mention, namely, the patient with pneumocystis and the patient with multiple infectious problems. First, the incidence of pneumocystis infections of the lung has increased considerably. This increase appears to be due primarily to the greater use of immunosuppressive drugs and to the prolongation of life of some patients suffering severe underlying disease such as leukemia. The diagnosis should be suspected in those with underlying lymphatic malignancy who manifest a persistent pulmonary infiltrate. The x-ray film usually shows lower lobe infiltrate but consolidation has been described. Ordinarily, one must resort to open lung biopsy to make the diagnosis. A "touch preparation" of the lung stained by the Gram-Weigert method will make these organisms visible. Repeat sputum sampling may yield the same organism in smear; thus far, the parasites have not been isolated in culture. Pentamidine appears to be beneficial in most clinically apparent pneumocystis infections.t 6 The concept of multiple organisms simultaneously producing diseases is at variance with old established concepts. One pathogen causing one disease is a dictum of OsIer that has withstood the test of time. Now, however, with compromised hosts who are often given immunosuppressive, adrenal glucocorticoid, or antibiotic drugs,this concept must be altered. For instance, we have seen a 30 year old patient with acute myelogenous leukemia on steroids develop simultaneous pseudomonas bacteremia, monilia esophagitis, and pulmonary pneumocystis infection; subsequently the patient developed an aspergillus lung infection, and toxoplasmosis of the central nervous system. Although this is a most unusual case, one must consider multiple organism invasion if a patient

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does not respond to appropriate therapy. In this case, the rapid development of acute pleuritic chest pain and a chest x-ray pattern consistent with pulmonary emboli lead to the diagnosis of the aspergillus infection. The central nervous system toxoplasmosis was mistaken for cryptococcus, as the cerebrospinal fluid was most consistent with previously described findings. This toxoplasmosis diagnosis was made at autopsy. A toxoplasmosis dye titer should have been done even though its occurrence is rare. Sulfadiazine (not other sulfas) and pyrithamine may have prolonged this patient's life a little longer. In these situations, the patient may be on as many as 10 drugs at one time. In desperately ill patients, these drugs may be used empirically on the presumptive rather than the actual diagnosis.

SUMMARY We are beginning to recognize a pattern of host deficiencies which promote superinfection with a specific pathogen or group of pathogens. Because life is being prolonged in greater number of damaged hosts, it is inevitable that such infections will prevent an increasing problem. Recognition of the relationship between pathogen and underlying disease pattern should permit earlier diagnosis and more effective management.

REFERENCES 1. Armstrong, D., Young, L., Meyer, R., et al.: Infectious complications of neoplastic disease. Med. Clin. N. Amer., 55:729-745, 1971. 2. Astom, K. E., Mancall, E. L., and Richardson, E. P.: Progressive multifocal leuko-encephalopathy: A hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin's disease. Brain, 81 :93-111,1958. 3. Cavanagh, J. B., Greenbaum, D., Marshall, D., et al.: Cerebral demyelination associated with disorders of the reticuloendothelial system. Lancet, 2:524-529,1959. 4. Dale, D. C., Ailing, D. W., and Wolff, S. M.: Cloxacillin chemoprophylaxis in the ChediakHigashi syndrome. J. Infect. Dis., 125:393-397, 1972. 5. Davis, T. A., Brunning, R. D., and Quie, P. G.: Polymorphonuclear leukocyte myeloperoxidase deficiency in a patient with myelomonocytic leukemia. New Eng. J. Med., 285:789-790,1971. 6. Good, R. A.: Disorders of the immune system. Hospital Practice, January, 1967, pp. 39-53. 7. Hirsch, J. S.: Host resistance to infectious disease. In Dubos, R. J., and Hirsch, J.: Bacterial and Mycotic Infections of Man. Philadelphia, J. B. Lippincott, 4th ed., 1965, pp. 170-180. 8. Klebanoff, S. J., and White, L. R.: Iodination defect in the leukocytes of a patient with chronic granulomatous disease of childhood. New Eng. J. Med., 280:460-466, 1969. 9. Lehrer, R. 1., Cline, M. J.: Leukocyte myeloperoxidase deficiency and disseminated candidasis: The role of myeloperoxidase in resistance to candida infection. J. Clin. Invest., 48:1478-1488,1969. 10. Lehrer, R. I., Goldbert, L. S., Apple, M. A., et al.: Refractory megaloblastic anemia with myeloperoxidase-deficient neutrophils. Ann. Intern. Med., 76:447-453, 1972. 11. Louria, D. B., Armstrong, D., and Smith, L. G.: Opportunistic infections: Special clinical consideration. The Second International Conference on Opportunistic Fungal Infection. 1972-1973, Springfield, Illinois, Charles C Thomas, in press. 12. Padgett, B. L., Walker, D.L., Rhein, Z., et al.: Cultivation of papova-like virus from human brain with progressive multifocalleucoencephalopathy. Lancet, 1 :1257-1260,1970. 13. Tattersall, M. H. N., Spiers, A. S. D., and Darrel, J. H.: Initial therapy with combination of five antibiotics in febrile patients with leukemia and neutropenia. The Lancet, 1: 162166, 1972.

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14. Waldmann, T. A.: Disorders ofimmunoglobulin metabolism. New Eng. J. Med., 281: 11701177,1969. 15. Weiner, L. P., Herndon, R. M., Narayan, 0., et aL: Isolation of virus related to SV40 from patients with progressive multifocalleukoencephalopathy. New Eng. J. Med.,286:385390, 1972. 16. Westun, K., Perera, D., and Schultz, M. S.: Pentamidine isothionate in the treatment of pneumocystis carinii pneumonia. Ann. Intern. Med., 73:695-702, 1970. Department of Medicine St. Michael's Medical Center 306 High Street Newark, New Jersey 07102