disseminated atypical mycobacterial infection in patients with hairy cell leukemia

Disseminated Atypical Mycobacterial Infection in Patients with Hairy Cell Leukemia

CHARLES BENNETT, M.D. JAMES VARDIMAN, M.D. HARVEY GOLOMB, M.D. Chicago, Illinois

From the Joint Section of Hematology/On- cology, Departments of Medicine and Pathology, University of Chicago, Pritzker School of Medi- cine and Michael Reese Medical Center, Chica- go, Illinois. This work was supported in part by United States Public Health Service Grant 19266, the Harry Greenberg Foundation, and the Thomas Moore Fund. Requests for reprints should be addressed to Dr. Charles Bennett, De- partment of Hematology/Oncology, University of Chicago Medical Center, 5841 South Maryland Avenue, Box 420, Chicago, Illinois 60637. Manu- script accepted April 10, 1985.

Disseminated atypical mycobacterial infections developed in nine of 188 patients with hairy cell leukemia who were seen over 10 years at the University of Chicago Hospital. Clinically, these patients had symptoms of fever and chills; an infiltrate was usually present on chest radiography. Invasive diagnostic studies, including thoracotomy and laparotomy, were necessary for confirmation of the diagnosis of atypical mycobacteria infection. Confirmatory culture specimens were obtained from lymph nodes, liver, and splenic tissue. Six patients had infections with Mycobacterium kansasii; two with M. avium-intracellulare; and one with M. chelonei. Treatment with multiple anti-tuberculosis drugs was initiated either empirically (six patients); after obtaining pathologic evidence of granuloma or acid-fast bacilli (two patients); or after obtaining a positive culture result (one patient). Five of the nine patients survived the infection and continued taking anti-tuberculosis drugs for total periods of nine months to two years. Awareness of the association between hairy cell leukemia and atypical mycobacteria infection, with early consideration of invasive diagnostic studies, as well as empiric anti-tuberculosis therapy, may prolong the survival time for many patients with hairy cell leukemia.

Hairy cell leukemia is an uncommon malignant disorder, accounting for only 2 percent of all leukemias. It is generally considered to be indolent, with infection the major cause of morbidity and mortality [ 1,2]. In several case reports, an association between hairy cell leukemia and atypical mycobacterial infection has been noted [3-61.

Disseminated atypical mycobacteria infection is uncommon; when it is noted, is often a fatal complication in patients with impaired immunity [7]. We have noted its occurrence in nine of 186 patients with hairy cell leukemia and examined the prognostic features, therapy, and long-term survival of these patients. To our knowledge, this is the first report that specifically addresses these issues in a large series of patients with hairy cell leukemia.

PATIENTS AND METHODS

We reviewed the clinical course of 186 patients referred to one of us (H.G.) for consultation between March 1974 and August 1, 1984. Diagnosis of hairy cell leukemia was documented by review of the peripheral blood smear and a bone marrow core biopsy specimen by a single hematopath- ologist (J.V.); splenectomy specimen was requested when available. Fol- low-up evaluations were carried out for all patients and took place over at least three months for all recent referrals. Eleven patients with presumed atypical mycobacteria infection were identified. Two patients were exclud- ed-one of these had no cultures sent and the second patient had negative

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ATYPICAL MYCOBACTERIUM AND HAIRY CELL LEUKEMIA-BENNETT ET AL

TABLE I Patient Characteristics

Patient Sex

Age at Time from Hairy Ceil Hairy Cell Diagnosis 01 Leukemia Diagnosis to Leukemia Therapy prior Hairy Cell Symptoms of Atypical to Atypical Mycobacterial Leukemia Mycobacterial Infection Infection Diagnosis

Acid-Fast Bacilli or Culture Sources of Atypical Granuloma Sources Mycobacferial Infection

1

2”

3t

47

5+

6

7t

88

9

M 65

M 30

M 60

M 28

F 46

M 33

M 57

M 49

M 42

6 months prior to hairy cell leukemia diagnosis

1 year, 2 months after hairy cell leukemia diagnosis

1 month prior to hairy cell leukemia

Half a month prior to hairy cell leukemia diagnosis

Half a month after hairy cell leukemia diagnosis

1.9 years after hairy cell leukemia diagnosis

Concomitant



Splenectomy Bone marrow

Splenectomy, chloram- None obtained bucil

Prednisone, splenecto- Supraclavicular my node

Prednisone, Cytoxan, Mediastinal node; Oncovin, methotrex- supraclavicular ate, leucovorin, cyto- node; hilar node; sine arabinoside liver; lung

Splenectomy Liver; spleen; lung

Chlorambucil, splenectomy

Lung

Prednisone, splenectomy

Chlorambucil, bleomy- tin, Velban, prednisone, splenectomy

Splenectomy

Abdominal nodes; spleen; liver

Hilar node; lung

Hilar node

Spleen (postmortem); hilar node (postmortem); sputum

Lung

Supraclavicular node

Nodes from mediastinum, hilum, supraclavicular area; liver

Liver; spleen; urine

Lung; blood

Spleen

Hilar node

Hilar node

* Died six years later with autopsy showing no evidence of atypical mycobacterial infection. t Describeb fully in [3,4]. - -

.

t Still receiving anti-tuberculosis therapy.

results of cultures from thoracotomy specimens (lung biopsy samples only) at three months. Both patients defer- vested with anti-tuberculosis therapy.

Charts were reviewed for hospitalizations and outpatient notes. Referring physicians were contacted and asked to provide information regarding atypical mycobacteria infection: state tuberculosis or hospital microbiology laborato- ries provided culture results and in vitro sensitivity analysis. Drugs tested for in vitro sensitivity were isoniazid, rifampin. para-amino salicylic acid, streptomycin, ethambutol, ethionamide, kanamycin, and pyrazinamide. Actuarial survival curves were obtained from the product limit (Kaplan-Meier) estimate. (Three of the patients with atypical mycobacteria infection were fully described in our earlier series [3,4] .)

RESULTS

The patients with hairy cell leukemia in our series included eight men and one woman (Table I) with documented disseminated atypical mycobacteria infection. The median age was 47 years. All patients had fever, chills, and fatigue, usually of less than two months’ duration. These

symptoms occurred from six months before to 56 months after the diagnosis of hairy cell leukemia. Therapy for the hairy cell leukemia prior to the diagnosis of atypical mycobacteria infection included splenectomy (eight patients), chemotherapy (four patients), and administration of steroids (four patients). All patients continued to be febrile despite empiric administration of antibacterial anti- biotics.

Noninvasive diagnostic tests that showed abnormalities included chest radiography demonstrating infiltrates (eight of nine patients) and gallium-67 scanning, which showed abnormal uptake (in three of five patients) in the lungs (one patient), supraclavicular nodal areas (one patient), and both lungs and the supraclavicular nodes (one patient). Pathologic evidence of granuloma or acid-fast bacilli was obtained in eight patients. In the remaining patient, an antemortem lung biopsy specimen and blood sample eventually showed M. kansasii infection-although the cultures showed growth after the patient’s death. All patients had atypical mycobacteria infection, as

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ATYPICAL MYCOBACTERIUM AND HAIRY CELL LEUKEMIA-BENNETT ET AL

Patient

Maximal Number of Anti-Tuberculosis

Drugs Used Atypical for Mycobacterial

Infection Organism Sensitivities Outcome

Time from Onset of Symptoms of Atypical

Mycobacterial infection to Beginning

Atypical Mycobacterial Infection Therapy

Duration of Anti- Tuberculosis Therapy

1

2”

3+

4+

M. kansasii

M. kansasii

M. kansasii

M. kansasii

M. kansasii

M. chelonei

M. kansasii

M. avium-intracellu- lare

M. avium-intracellu- lare

Completely sensitive except to isoniazid

Sensitive except to isoniazid, para-amino salicylic acid, ethambutol

Sensitive only to ethionamide

Sensitive only to ethambutol, streptomycin, para-amino salicylic acid, ethionamide, rifampin

Sensitive to all but isoniazid, para-amino salicylic acid

Resistant to all drugs tested

Sensitive only to rifampin



Died 3 months 3.5 months

Died 6 weeks 2 weeks

Died 8 weeks 2.5 years

Survived

Died

Survived

Survived

Survived

2 weeks

8 weeks

1 week

4 weeks

6 weeks

2 years, 3 months

7 weeks

14-t months

1 l-t months

9 months

confirmed on blood culture (one patient), urine culture (one patient), sputum culture (one patient), and invasive tests yielding tissue from lymph nodes, spleen, liver, and lungs (nine patients). Invasive tests included thoracotomy, lymph node biopsy, laparotomy, and bronchoscopy. High- yield procedures were lymph node biopsy in four patients (all four patients had positive results of cultures) and laparotomy in four patients (three patients had positive results of cultures). Laparotomy provided culture specimens of atypical mycobacteria infection from the liver, spleen, and intra-abdominal lymph nodes. Low-yield invasive procedures were bronchoscopy (no positive culture results in three patients) and thoracotomy for culture specimens of lung parenchyma (one positive culture result in five patients). All areas of increased uptake on gallium-67 scanning yielded culture specimens for atypical mycobacteria infection when the tissue was obtained by invasive procedures (three of three patients).

All patients were treated with three to six anti-tuberculosis drugs; eight patients had therapy prior to confirma-

tion of atypical mycobacteria infection by culture. The drugs used included isoniazid and rifampin (all patients) and at least one of the following: ethambutol, ethionamide, pyrazinamide, kanamycin, para-amino salicylic acid, and streptomycin. In no instance was in vitro sensitivity analysis available prior to the initiation of therapy.

Of the five patients who survived the atypical mycobacteria infection, two are still undergoing therapy (at 11 and 14 months). The other three were treated for nine months, two years, and two and a half years. Those four patients who died with atypical mycobacteria infection lived for a median of five and a half weeks after the start of anti- tuberculosis therapy (range two to 14 weeks).

M. avium-intracellular-e was found in two patients; both survived the infection despite in vitro resistance to all anti- tuberculosis drugs that were used. One of these patients discontinued his therapy on his own at nine months and has no evidence of atypical mycobacteria infection one year later. The second patient is still receiving five-drug therapy; he has no symptoms and chest radiography


showed resolution of his original infiltrate after 11 months of therapy. Of six patients who had M. kansasii infections, three died. All three had sensitive organisms in vitro; only one of the survivors had sensitive organisms. One patient died with M. chelonei infection. In vitro studies showed the organism to be completely resistant.

Patients who died with atypical mycobacteria infection tended to be younger than those who survived (median age, 35.5 versus 47 years), had prior chemotherapy for their hairy cell leukemia (three of four versus one of five), and began anti-tuberculosis therapy at a longer interval after the start of symptoms (median, eight weeks versus four weeks). The survivors and the nonsurvivors had a similar incidence of prior documented infections, splenectomy, and prior steroid therapy for their hairy cell leukemia.

Anti-tuberculosis therapy was started empirically in two patients and after pathologic evidence of granulomas or acid-fast bacilli was obtained in six patients. The remaining patient (who died with atypical mycobacteria infection) began treatment after a culture-positive sputum specimen for M. kansasii was obtained.

The five patients who survived the atypical mycObaC- teria infection continued to take anti-tuberculosis drugs for at least nine months. Stable findings on chest radiography and absence of symptoms were the indications for cessa- tion of therapy in all but one patient, who had no symp- tomsand a stable resutt of chest .radiography and who chose to discontinue his therapy at nine months of a planned two-year course. Three patients finished a course of therapy; one of those was treated again empirically after six months without therapy, because of recurrence of fever, although no positive culture results were obtained. At autopsy (three years after therapy was empirically resumed), no evidence of atypical mycobacteria infection was found. The other two patients continue without therapy for atypical mycobacteria infection at one year and four years of follow-up. The four patients who died with atypical mycobacteria infection did so within seven months after the onset of symptoms.

Complications of anti-tuberculosis therapy included kanamycin-induced ototoxicity (one patient), depression (three patients), pyrazinamide-induced hyperuricemia (three patients), ethionamide-induced hypothyroidism (one patient), liver function abnormalities (one patient), and a maculopapular skin rash (four patients).

COMMENTS

In general, disseminated atypical mycobacterial infections are uncommon and are usually fatal. Relatively few well- documented infections caused by the most common atypical mycobacteria, M. kansasii and M. avium-intracellulare, have been reported [7-lo]; with most infections noted in patients receiving immunosuppressive therapy or patients with hematologic disease [3, Ill. Outside our

ATYPICAL MYCOBACTERIUM AND HAIRY CELL LEUKEMIA-BENNETT E-i AL

hospital, there have been nine reported cases in patients with hairy cell leukemia [6,8,9,12-141. Atypical mycobacteria infection in association with hairy cell leukemia has been noted predominantly in Texas and Chicago; it is rare in Los Angeles. This reflects the fact that Texas and Chicago, unlike Los Angeles, are areas where atypical mycobacteria are endemic [2,3,5,12,15].

All of our nine patients had clinical characteristics of fever and chills, usually of less than two months’ duration, and eight had abnormalities on chest radiography. These characteristics have been noted in prior case reports of atypical mycobacteria infection in patients with hairy cell leukemia [5,6]. Six of our nine patients had received corticosteroids and/or cytotoxic chemotherapy for treatment of their hairy cell leukemia. Such therapy may be an additional factor in the development of atypical mycobacteria infection in these patients. Bouza et al [ 161 have postulated that the immune defects that predispose to atypical mycobacteria infection in these patients are even further altered with steroids and/or cytotoxic chemotherapy. Eight of our nine patients also underwent splenectomy for treatment of their hairy cell leukemia. It is doubtful that this procedure was an additional predisposing factor in the development of atypical mycobacteria infection. Post- splenectomy infections usually occur in infants; they are infrequently noted in adults. When seen, the infecting organism most often recovered is Diplococcus pneumo- nia; less commonly Meningococcus, Escherichia coli, Hemophilus influenzae, and Staphylococcus are found. No association of atypical mycobacteria infection has been noted in splenectomized patients [ 17,181.

In eight of the nine patients, therapy with anti-tuberculosis drugs was initiated prior to identification of the organism by culture. Positive identification was obtained via invasive procedures in all patients; high-yield procedures being lymph node culture or laparotomy. Bronchoscopy was uniformly nondiagnostic. Lung parenchyma obtained at thoracotomy was also of low yield; however, the lymph nodes obtained during thoracotomy provided culture identification of atypical mycobacteria infection in four of five patients.

Disseminated infection with M. avium-intracellulare has been noted in patients with other hematologic malig- nancies, hairy cell leukemia, and AIDS [3,4,6,19]. Sus- ceptibility testing in vitro of M. avium-intracellulare shows marked resistance to anti-tuberculosis drugs [20-221, and there are numerous reports of poor clinical responses to therapy by patients infected with this organism. In prior studies of patients with pulmonary infection due to M. avium-intracellulare, multiple anti-tuberculosis drug therapy was effective in symptomatic patients when they were treated for nine to 24 months [20]. Similar results were noted in five patients with extrapulmonary disease who were treated with long-term antituberculosis therapy [2 11. Two of our patients had M. avium-intracellulare infections;


ATYPICAL MYCOBACTERIUM AND HAIRY CELL LEUKEMIA--BENNETT ET AL

both survived the infection, upon being treated with multiple anti-tuberculosis drugs shortly after the onset of symptoms, despite in vitro testing that showed completely resistant organisms.

Patients with disease due to M. kansasii usually have systemic symptoms and radiographic evidence of cavitary lung lesions [23]. In vitro sensitivity analysis shows this organism to be sensitive to anti-tuberculosis drugs, and clinical studies generally show an excellent therapeutic response in nonimmunocompromised patients [23-271. However, three of our six patients who had M. kansasii infections died with active disease despite therapy with multiple anti-tuberculosis drugs, and despite in vitro testing that showed completely sensitive organisms. These patients had constitutional symptoms over a longer period before being treated than did those who survived, even though two of the survivors had resistant organisms.

In patients with disease caused by M. chelonei, soft tissue and skin infections are usually seen, whereas pulmonary infection is rare. In vitro testing usually shows the organisms to be resistant to all anti-tuberculosis drugs, and poor responses to therapy have been noted clinically [28]. Recently, investigators have concluded that patients who cannot undergo surgical excision of the infected site may benefit from therapy with amikacin, doxycycline, sulfamethizole, and some of the newer cephalosporins [29,30]. In our patient with M. chelonei infection, an

infiltrate was seen on chest radiography and the organism was identified on blood culture and lung biopsy. The M. chelonei was completely resistant in vitro, and the patient died within seven weeks with active disease despite receiving multiple anti-tuberculosis drugs.

In conclusion, disseminated atypical mycobacterial infection occurs in about 5 percent of patients with hairy cell leukemia and is often a fatal infection. Invasive diagnostic studies-including thoracotomy with lymph nodes-are important in providing confirmatory evidence of atypical mycobacteria infection. Bronchoscopy, however, has a low yield in these patients. Gallium-67 scanning, although nonspecific, may be useful in directing the physician to a specific site for biopsy and culture. Early treatment with multiple anti-tuberculosis drugs is important in influencing survival. Even if in vitro sensitivity analysis indicates highly resistant organisms, a cure can be obtained in patients with atypical mycobacteria infection who are given early therapy prior to culture confirmation and in whom therapy is continued for nine months to two and a half years.

ACKNOWLEDGMENT

We would like to thank Karen Daly, R.N., Oncology Nurse, for the coordination of patient material, Margaret Johnson for data collection, and Shirley Perry for secretarial assis- tance.

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disseminated atypical mycobacterial infection in patients with hairy cell leukemia

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