Tuberculosis After Jejunoileal Bypass for Obesity ROBERT M. BRUCE, M.D.; and LESLIE WISE, M.D.; St. Louis, Missouri
One hundred patients who underwent jejunoileal bypass for obesity were followed for a mean period of 2V2 years. Four patients developed a clinical illness that resembled a systemic form of tuberculosis during the first postoperative year. This incidence exceeds that found in the general population by sixtyfold. Any patient with jejunoileal bypass who develops an illness with accelerated weight loss, enlarged lymph nodes, and unexplained fever with chills should be suspected of having tuberculosis. Aggressive diagnostic measures are required. Treatment with isoniazid and ethambutol at usual doses can be successful, but blood levels should be measured to confirm adequacy until additional information becomes available.
E N T H U S I A S M for the jejunoileal bypass treatment of intractable obesity has diminished because of postoperative complications. Thromboembolism, wound infection, and pneumonia are greater risks for obese patients who undergo major surgery than for others, but additional complications follow jejunoileal bypass (1). These include lifethreatening hepatic insufficiency, profound electrolyte imbalance, and jejunal intussusception. Less serious complications include stones in the kidneys and gallbladder, the blind-loop syndrome, polyarthropathy, and alopecia. Seven patients have been reported previously with tuberculosis after intestinal bypass (2-5). We report here four additional patients who developed tuberculosis from a group of 101 consecutive patients whose average followup was 2.6 years after bypass. Case Reports CASE 1
A 28-year-old woman who weighed 172 kg underwent jejunoileal bypass in August 1973. Her course was uncomplicated for 6 months postoperatively until she developed fever, cervical adenopathy, and accelerated weight loss. Therapy with broad spectrum antibiotics was ineffective. An exudative pleural effusion developed on the right that contained predominantly mononuclear cells. Intermediate strength tuberculin skin test (unreactive 6 months earlier) resulted in 20-mm induration at 48 h. She was treated with isoniazid, 600 mg, and ethambutol, 1500 mg daily, and fever resolved 8 days later. Three cultures of sputum, two of urine, and one of liver on Middlebrook 7H-11 medium were negative. Two months later the patient developed ankle edema and jaundice. Laparotomy showed multiple gallstones. Cholecystectomy was done and the small bowel reanastomosed. Antituberculous therapy was continued postoperatively, but fever continued and multiple abdominal abscesses developed. One month later she died of pulmonary emboli. Au• From the Departments of Internal Medicine and Surgery, Washington University Medical Center; St. Louis, Missouri.
574
Downloaded From: https://annals.org/ by a La Trobe University User on 08/03/2018
topsy revealed caseating granulomas in lymph nodes draining the right lung and the porta hepatis, but acid-fast bacilli and fungi were not found. Comment: E v i d e n c e for s y s t e m i c tuberculosis i n c l u d e d the presence o f caseating g r a n u l o m a s in l y m p h n o d e s , lung, a n d liver together w i t h c o m p a t i b l e clinical pattern, skin test conversion, a n d favorable response t o therapy. D e a t h w a s related t o sepsis a n d p u l m o n a r y t h r o m b o e m bolism. CASE 2
A 24-year-old woman who weighed 118 kg underwent jejunoileal bypass in March 1973 and subsequently lost 59 kg. Ten months later fever, night sweats, and productive cough occurred with left-sided pleuritic pain. Chest roentgenogram showed left hilar and right paratracheal adenopathy. Skin tests with PPD-T (5 and 100 tuberculin units), B, G, and Y were negative, but she reacted to Candida, mumps, and streptokinasestreptodornase antigens. Biopsy of a mediastinal lymph node showed noncaseating granulomas on microscopic examination. Mycobacterium tuberculosis was recovered on culture from the lymph node and from washings obtained at bronchoscopy. Fever subsided soon after beginning daily treatment with streptomycin, 900 mg intramuscularly, isoniazid, 600 mg, and ethambutol, 1200 mg orally. She was well for 2 months on medication, but a decision was made for reanastomosis. The hilar and paratracheal adenopathy resolved, and she gained 38 kg during the next year. Comment: Tuberculosis w a s proved b y t h e recovery o f o r g a n i s m s o n cultures obtained from bronchial w a s h i n g s and mediastinal l y m p h n o d e biopsy. CASE 3
A 40-year-old woman who weighed 124 kg underwent jejunoileal bypass and lost 52 kg in 7 months, after which lowgrade fever and night sweats appeared. Fever continued for several months, and intermediate strength PPD-T test (negative 5 years earlier) resulted in 25-mm induration at 48 h. Sputum cultures were negative for M. tuberculosis, and liver biopsy showed noncaseating granulomas. She was treated intramuscularly with isoniazid, 300 mg, and streptomycin, 1 g daily. Within 2 weeks fever defervesced, and she began to feel well. After 1 month, treatment was changed to oral isoniazid, 300 mg, and ethambutol, 1000 mg daily. She continues well to the present. Comment: T h e diagnosis o f tuberculosis s e e m s highly probable from t h e clinical pattern w i t h skin test conversion, g r a n u l o m a s o n liver biopsy, a n d response t o antituberculous m e d i c a t i o n . CASE 4
A 25-year-old woman (131 kg) underwent jejunoileal bypass. She lost 30 kg during the first 7 months after bypass and an additional 30 kg during the next 3 months. She developed shaking chills, night sweats, and fever as high as 40 °C. Intermediate strength PPD-T skin test was unreactive (tine test had been positive in 1974). Streptokinase-streptodornase skin test resulted in 10-mm induration at 48 h. Cultures of sputum, gastric washings, and urine were negative for mycobacteria and fungi. Liver biopsy showed noncaseating granulomas that were found to contain acid-fast organisms. After a short course of daily Annals of Internal Medicine 87:574-576, 1977
Table 1. Clinical Features in Tuberculosis After Intestinal Bypass*
Authors
Age
Sex
Race
57 55 21
F F M
B W W
22 36 160
Pickleman et al (4)
42
F
W
45
Wasson and Harris (5) Battershill (6)
NS
NS
NS
NS
NS
Bruce and Wisef
NS 28
Outcome
Treatment
Symptoms
Sites Involved
Organisms Found
NS NS Accelerated weight loss Chills, fever
Cervical nodes Cervical nodes Lung and hilar nodes Cervical nodes
NS NS Bronchial washings Lymph node
"Medical" "Medical" "Drug"
Successful Successful Successful
SM, INH, EMB
NS
NS
Lung
Sputum
NS
45
NS
Calcaneus
NS
INH, EMB, RMP "Chemotherapy"
Healing of draining site NS
NS F
NS B
56 72
NS Chills, fever, weakness, accelerated weight loss
Lung Pleural, hilar, and hepatic nodes
Sputum Negative sputum, urine, liver cultures
NS INH, EMB
24
F
W
59
Fever, night sweats
Mediastinal nodes
(SM), I N H , EMB
40
F
W
52
Fever, night sweats, malaise
Liver
(SM), INH, EMB
Resolution of fever, sweats
25
F
W
68
Fever, night sweats, accelerated weight loss
Liver
Lymph node, bronchial washing Negative sputum and liver cultures In hepatic granulomas
Healing granuloma NS Good clinical response to antituberculous therapy. Died of multiple pulmonary emboli Regression of adenopathy
(SM), I N H , EMB
Resolution of fever, sweats
yrs Wills (2, 3)
Weight Lost kg
* NS = not stated; B = black; W = white; SM = streptomycin; INH = isoniazid; EMB = ethambutol; RMP = rifampin. t Authors of this paper.
intramuscular isoniazid, 300 mg, and streptomycin, 1 g, she became afebrile and felt well. She received isoniazid and ethambutol orally and has remained well since.
Comment: Tuberculosis, suspected from the clinical course, was confirmed by presence of acid-fast bacilli in hepatic granulomas. Discussion
One hundred one patients underwent jejunoileal bypass between March 1972 and May 1975: 7 cm to 10 cm of jejunum was anastomosed end to end to 30 cm to 37 cm of terminal ileum. The proximal end of the bypassed segment was closed and the distal portion anastomosed end to side to the cecum. Postoperative evaluation of these patients averaged 2.6 years (range, 1 to 4 years). Tuberculosis was proved by the presence of the organisms in two patients and was presumed in two from clinical, histologic, and therapeutic findings. The frequency of tuberculosis in this group contrasts sharply with that in the general population. The new case rate for tuberculosis in women in St. Louis during the period covered by this report was 12/100 000 per year. If we consider only two patients as having proven tuberculosis, the incidence exceeds by sixty-threefold that in the general population (chi-square = 1948; P < 0.0005). Table 1 compares the clinical and laboratory features of our four patients with seven cases previously reported. Only two of these 11 patients had pulmonary tuberculo-
sis. Disease in the lymph nodes was manifest in six patients, and one had an exudative pleural effusion. Hepatic granulomas were documented in two, and skeletal tuberculosis was presumed in another. The pattern of progressive systemic involvement is an unusual feature of tuberculosis in this group. Tuberculin skin tests were not uniformly helpful. Organisms were cultured from one patient (Case 2) whose skin reaction was persistently negative during 26 months of illness. She was not lymphopenic, and skin reactivity was present for other antigens. Another patient, unreactive to tuberculin (Case 4), was found to have acid-fast bacilli in hepatic granulomas. The other two patients Table 2. Blood Levels of Oral Antituberculous Drugs in Patients Who Underwent Jejunoileal Bypass
Isoniazid (600 mg)*
< Case 2 10 minutes 20 minutes 30 minutes 60 minutes Case 4 3h
Ethambutol (25mg/kg)*
Rifampin (600 mg)*
ng/ml
•
0.1 0.2 0.8 8.0
3.0 6.0 6.0 6.0
4.8 0 0 0
6.4
4.0
0
* Therapeutic range: isoniazid, 0.4 to 4.0 fig/m\; ethambutol, 3 to 12 fig/ml', rifampin, 10 to 40 yug/ml. Bruce and Wise • Tuberculosis After Intestinal Bypass
Downloaded From: https://annals.org/ by a La Trobe University User on 08/03/2018
575
both reacted to tuberculin. Lymphocyte-blast transformation gave normal or exaggerated responses to nonspecific mitogens. Challenge with specific antigens or mixed leukocytes, however, produced positive but less energetic responses than in normal control subjects. Many patients developed transient lymphopenia after bypass, but this persisted only in a few. Lymphopenia was no more severe in those patients who developed tuberculosis after bypass than in the others (1959 and 1919 lymphocytes/mm 3 , respectively). Caseating granulomas were found in the tissues of only one of our four patients. Pathologic material from our other three cases showed noncaseating granulomas. It is generally accepted that the extent of caseation is determined by antigenic load and vigor of cellular immune response. In-vitro reduced responses to specific antigens in patients who have undergone bypass suggest that these patients may not defend themselves as well against tuberculosis as other patients. Malnutrition is an established risk factor for development of tuberculosis associated with abnormal immunoreactivity (7, 8). Harland (9) has reported a diminished responsiveness to tuberculin in malnourished children as compared to healthy children after B C G inoculation. Whether the increased risk of tuberculosis after bypass results from malnutrition or from other alterations of host defenses is not known. All four of our patients developed symptoms of tuberculosis within 10 months after bypass coincident with the phase of rapid weight loss. The patient who has undergone bypass may lack the absorptive intestinal surface necessary for effective antituberculous therapy by the oral route. These drugs are absorbed in the stomach, duodenum, or upper jejunum. Table 2 indicates the blood levels of drugs after oral administration. Adequate levels of isoniazid were achieved in two patients with conventional oral doses. The clearance of isoniazid measured in the urine was no different in patients who had undergone bypass than in normal subjects. Liver enzymes were monitored frequently during isoniazid administration to our patients, but all findings were normal. Ethambutol is absorbed in the stomach and proximal jejunum. Two of our patients achieved therapeutic serum levels of ethambutol only after the administration of high doses (25 mg/kg). In both of these patients ethambutol was undetectable in the urine 12 h later. This contrasts with the persistence of ethambutol in the urine of normal subjects for 60 to 72 h after ingestion. One patient studied
576
by Wasson and Harris (5) had a serum level below 1 ju,g/ ml 2 and 4 h after a dose of 13.6 mg/kg. Rifampin participates in an enterohepatic circulation. This drug appeared early in the blood of one of our patients but then rapidly disappeared, suggesting that proximal absorption had occurred normally but the drug had been lost after biliary excretion. Streptomycin given parenterally is excreted by the kidneys. One patient had normal renal function and was given 15 m g / k g • day. Another patient h a d undergone unilateral nephrectomy and was stabilized on a dosage of 15 m g / k g • 36 h. Both patients had elevated blood levels (46 and 52 u g / m l ; usual therapeutic range, 10 to 40), and both developed mild vestibular toxicity that cleared after therapy stopped. Our patients who were treated with isoniazid and ethambutol together or in combination for brief periods with streptomycin improved clinically and radiographically. Conventional therapy with these oral agents thus seems to be adequate, but measurement of serum levels is necessary if one is to document adequate intestinal absorption. If one plans to use rifampin, measurement of the postabsorptive blood levels is essential. A C K N O W L E D G M E N T S : The authors thank J. Kenneth McKlatchey, Ph.D., for measuring the antituberculous drug levels at National Jewish Hospital and Research Center, Denver, Colorado; and John A. Pierce, M.D., for helpful guidance. Grant support: in part by Grant # R R 00036 from the National Institutes of Health, Bethesda, Maryland. Received 6 December 1976; revision accepted 18 July 1977. • Requests for reprints should be addressed to Robert M. Bruce, M.D.; Pulmonary Division, Washington University, 660 South Euclid Ave.; St. Louis, MO 63110.
References 1. W I S E L: Iatrogenic short bowel syndrome: surgical treatment of morbid exogenous obesity. Pract Surg 2:176-214, 1975 2. W I L L S CE JR: Jejuno-ileostomy for obesity. J Med Assoc Ga 58:456-461, 1969 3. W I L L S CE J R : Tuberculosis after jejunoileal bypass (letter). JAMA 235:1425, 1976 4. P I C K L E M A N JR, E V A N S LS, K A N E JM, F R E E A R K RJ: Tuberculosis after
jejunoileal bypass for obesity. JAMA 22>A:1AA, 1975 5. WASSON KR, HARRIS JO: The treatment of tuberculosis (TB) in the presence of malabsorption syndromes (MAS). (Abstract) Am Rev Resp Dis 113:51, 1976 6. BATTERSHILL JH: Tuberculosis after intestinal bypass surgery for obesity (letter). Chest 70:318, 1976 7. L A W DK, D U D R I C K SJ, ABDOU NI: The effects of protein calorie malnutrition on immune competence of the surgical patient. Surg Gynecol Obstet 139:257-266, 1974 8. BISTRIAN BR, BLACKBURN G L , SCRIMSHAW NS, F L A T T J-P: Cellular
immunity in semistarved states in hospitalized adults. Am J Clin Nutr 28:1148-1155, 1975 9. H A R L A N D PSEG: Tuberculin reactions in malnourished children. Lancet 2:719-721, 1965
November 1977 • Annals of Internal Medicine • Volume 87 • Number 5
Downloaded From: https://annals.org/ by a La Trobe University User on 08/03/2018
One hundred patients who underwent jejunoileal bypass for obesity were followed for a mean period of 2V2 years. Four patients developed a clinical illness that resembled a systemic form of tuberculosis during the first postoperative year. This incidence exceeds that found in the general population by sixtyfold. Any patient with jejunoileal bypass who develops an illness with accelerated weight loss, enlarged lymph nodes, and unexplained fever with chills should be suspected of having tuberculosis. Aggressive diagnostic measures are required. Treatment with isoniazid and ethambutol at usual doses can be successful, but blood levels should be measured to confirm adequacy until additional information becomes available.
E N T H U S I A S M for the jejunoileal bypass treatment of intractable obesity has diminished because of postoperative complications. Thromboembolism, wound infection, and pneumonia are greater risks for obese patients who undergo major surgery than for others, but additional complications follow jejunoileal bypass (1). These include lifethreatening hepatic insufficiency, profound electrolyte imbalance, and jejunal intussusception. Less serious complications include stones in the kidneys and gallbladder, the blind-loop syndrome, polyarthropathy, and alopecia. Seven patients have been reported previously with tuberculosis after intestinal bypass (2-5). We report here four additional patients who developed tuberculosis from a group of 101 consecutive patients whose average followup was 2.6 years after bypass. Case Reports CASE 1
A 28-year-old woman who weighed 172 kg underwent jejunoileal bypass in August 1973. Her course was uncomplicated for 6 months postoperatively until she developed fever, cervical adenopathy, and accelerated weight loss. Therapy with broad spectrum antibiotics was ineffective. An exudative pleural effusion developed on the right that contained predominantly mononuclear cells. Intermediate strength tuberculin skin test (unreactive 6 months earlier) resulted in 20-mm induration at 48 h. She was treated with isoniazid, 600 mg, and ethambutol, 1500 mg daily, and fever resolved 8 days later. Three cultures of sputum, two of urine, and one of liver on Middlebrook 7H-11 medium were negative. Two months later the patient developed ankle edema and jaundice. Laparotomy showed multiple gallstones. Cholecystectomy was done and the small bowel reanastomosed. Antituberculous therapy was continued postoperatively, but fever continued and multiple abdominal abscesses developed. One month later she died of pulmonary emboli. Au• From the Departments of Internal Medicine and Surgery, Washington University Medical Center; St. Louis, Missouri.
574
Downloaded From: https://annals.org/ by a La Trobe University User on 08/03/2018
topsy revealed caseating granulomas in lymph nodes draining the right lung and the porta hepatis, but acid-fast bacilli and fungi were not found. Comment: E v i d e n c e for s y s t e m i c tuberculosis i n c l u d e d the presence o f caseating g r a n u l o m a s in l y m p h n o d e s , lung, a n d liver together w i t h c o m p a t i b l e clinical pattern, skin test conversion, a n d favorable response t o therapy. D e a t h w a s related t o sepsis a n d p u l m o n a r y t h r o m b o e m bolism. CASE 2
A 24-year-old woman who weighed 118 kg underwent jejunoileal bypass in March 1973 and subsequently lost 59 kg. Ten months later fever, night sweats, and productive cough occurred with left-sided pleuritic pain. Chest roentgenogram showed left hilar and right paratracheal adenopathy. Skin tests with PPD-T (5 and 100 tuberculin units), B, G, and Y were negative, but she reacted to Candida, mumps, and streptokinasestreptodornase antigens. Biopsy of a mediastinal lymph node showed noncaseating granulomas on microscopic examination. Mycobacterium tuberculosis was recovered on culture from the lymph node and from washings obtained at bronchoscopy. Fever subsided soon after beginning daily treatment with streptomycin, 900 mg intramuscularly, isoniazid, 600 mg, and ethambutol, 1200 mg orally. She was well for 2 months on medication, but a decision was made for reanastomosis. The hilar and paratracheal adenopathy resolved, and she gained 38 kg during the next year. Comment: Tuberculosis w a s proved b y t h e recovery o f o r g a n i s m s o n cultures obtained from bronchial w a s h i n g s and mediastinal l y m p h n o d e biopsy. CASE 3
A 40-year-old woman who weighed 124 kg underwent jejunoileal bypass and lost 52 kg in 7 months, after which lowgrade fever and night sweats appeared. Fever continued for several months, and intermediate strength PPD-T test (negative 5 years earlier) resulted in 25-mm induration at 48 h. Sputum cultures were negative for M. tuberculosis, and liver biopsy showed noncaseating granulomas. She was treated intramuscularly with isoniazid, 300 mg, and streptomycin, 1 g daily. Within 2 weeks fever defervesced, and she began to feel well. After 1 month, treatment was changed to oral isoniazid, 300 mg, and ethambutol, 1000 mg daily. She continues well to the present. Comment: T h e diagnosis o f tuberculosis s e e m s highly probable from t h e clinical pattern w i t h skin test conversion, g r a n u l o m a s o n liver biopsy, a n d response t o antituberculous m e d i c a t i o n . CASE 4
A 25-year-old woman (131 kg) underwent jejunoileal bypass. She lost 30 kg during the first 7 months after bypass and an additional 30 kg during the next 3 months. She developed shaking chills, night sweats, and fever as high as 40 °C. Intermediate strength PPD-T skin test was unreactive (tine test had been positive in 1974). Streptokinase-streptodornase skin test resulted in 10-mm induration at 48 h. Cultures of sputum, gastric washings, and urine were negative for mycobacteria and fungi. Liver biopsy showed noncaseating granulomas that were found to contain acid-fast organisms. After a short course of daily Annals of Internal Medicine 87:574-576, 1977
Table 1. Clinical Features in Tuberculosis After Intestinal Bypass*
Authors
Age
Sex
Race
57 55 21
F F M
B W W
22 36 160
Pickleman et al (4)
42
F
W
45
Wasson and Harris (5) Battershill (6)
NS
NS
NS
NS
NS
Bruce and Wisef
NS 28
Outcome
Treatment
Symptoms
Sites Involved
Organisms Found
NS NS Accelerated weight loss Chills, fever
Cervical nodes Cervical nodes Lung and hilar nodes Cervical nodes
NS NS Bronchial washings Lymph node
"Medical" "Medical" "Drug"
Successful Successful Successful
SM, INH, EMB
NS
NS
Lung
Sputum
NS
45
NS
Calcaneus
NS
INH, EMB, RMP "Chemotherapy"
Healing of draining site NS
NS F
NS B
56 72
NS Chills, fever, weakness, accelerated weight loss
Lung Pleural, hilar, and hepatic nodes
Sputum Negative sputum, urine, liver cultures
NS INH, EMB
24
F
W
59
Fever, night sweats
Mediastinal nodes
(SM), I N H , EMB
40
F
W
52
Fever, night sweats, malaise
Liver
(SM), INH, EMB
Resolution of fever, sweats
25
F
W
68
Fever, night sweats, accelerated weight loss
Liver
Lymph node, bronchial washing Negative sputum and liver cultures In hepatic granulomas
Healing granuloma NS Good clinical response to antituberculous therapy. Died of multiple pulmonary emboli Regression of adenopathy
(SM), I N H , EMB
Resolution of fever, sweats
yrs Wills (2, 3)
Weight Lost kg
* NS = not stated; B = black; W = white; SM = streptomycin; INH = isoniazid; EMB = ethambutol; RMP = rifampin. t Authors of this paper.
intramuscular isoniazid, 300 mg, and streptomycin, 1 g, she became afebrile and felt well. She received isoniazid and ethambutol orally and has remained well since.
Comment: Tuberculosis, suspected from the clinical course, was confirmed by presence of acid-fast bacilli in hepatic granulomas. Discussion
One hundred one patients underwent jejunoileal bypass between March 1972 and May 1975: 7 cm to 10 cm of jejunum was anastomosed end to end to 30 cm to 37 cm of terminal ileum. The proximal end of the bypassed segment was closed and the distal portion anastomosed end to side to the cecum. Postoperative evaluation of these patients averaged 2.6 years (range, 1 to 4 years). Tuberculosis was proved by the presence of the organisms in two patients and was presumed in two from clinical, histologic, and therapeutic findings. The frequency of tuberculosis in this group contrasts sharply with that in the general population. The new case rate for tuberculosis in women in St. Louis during the period covered by this report was 12/100 000 per year. If we consider only two patients as having proven tuberculosis, the incidence exceeds by sixty-threefold that in the general population (chi-square = 1948; P < 0.0005). Table 1 compares the clinical and laboratory features of our four patients with seven cases previously reported. Only two of these 11 patients had pulmonary tuberculo-
sis. Disease in the lymph nodes was manifest in six patients, and one had an exudative pleural effusion. Hepatic granulomas were documented in two, and skeletal tuberculosis was presumed in another. The pattern of progressive systemic involvement is an unusual feature of tuberculosis in this group. Tuberculin skin tests were not uniformly helpful. Organisms were cultured from one patient (Case 2) whose skin reaction was persistently negative during 26 months of illness. She was not lymphopenic, and skin reactivity was present for other antigens. Another patient, unreactive to tuberculin (Case 4), was found to have acid-fast bacilli in hepatic granulomas. The other two patients Table 2. Blood Levels of Oral Antituberculous Drugs in Patients Who Underwent Jejunoileal Bypass
Isoniazid (600 mg)*
< Case 2 10 minutes 20 minutes 30 minutes 60 minutes Case 4 3h
Ethambutol (25mg/kg)*
Rifampin (600 mg)*
ng/ml
•
0.1 0.2 0.8 8.0
3.0 6.0 6.0 6.0
4.8 0 0 0
6.4
4.0
0
* Therapeutic range: isoniazid, 0.4 to 4.0 fig/m\; ethambutol, 3 to 12 fig/ml', rifampin, 10 to 40 yug/ml. Bruce and Wise • Tuberculosis After Intestinal Bypass
Downloaded From: https://annals.org/ by a La Trobe University User on 08/03/2018
575
both reacted to tuberculin. Lymphocyte-blast transformation gave normal or exaggerated responses to nonspecific mitogens. Challenge with specific antigens or mixed leukocytes, however, produced positive but less energetic responses than in normal control subjects. Many patients developed transient lymphopenia after bypass, but this persisted only in a few. Lymphopenia was no more severe in those patients who developed tuberculosis after bypass than in the others (1959 and 1919 lymphocytes/mm 3 , respectively). Caseating granulomas were found in the tissues of only one of our four patients. Pathologic material from our other three cases showed noncaseating granulomas. It is generally accepted that the extent of caseation is determined by antigenic load and vigor of cellular immune response. In-vitro reduced responses to specific antigens in patients who have undergone bypass suggest that these patients may not defend themselves as well against tuberculosis as other patients. Malnutrition is an established risk factor for development of tuberculosis associated with abnormal immunoreactivity (7, 8). Harland (9) has reported a diminished responsiveness to tuberculin in malnourished children as compared to healthy children after B C G inoculation. Whether the increased risk of tuberculosis after bypass results from malnutrition or from other alterations of host defenses is not known. All four of our patients developed symptoms of tuberculosis within 10 months after bypass coincident with the phase of rapid weight loss. The patient who has undergone bypass may lack the absorptive intestinal surface necessary for effective antituberculous therapy by the oral route. These drugs are absorbed in the stomach, duodenum, or upper jejunum. Table 2 indicates the blood levels of drugs after oral administration. Adequate levels of isoniazid were achieved in two patients with conventional oral doses. The clearance of isoniazid measured in the urine was no different in patients who had undergone bypass than in normal subjects. Liver enzymes were monitored frequently during isoniazid administration to our patients, but all findings were normal. Ethambutol is absorbed in the stomach and proximal jejunum. Two of our patients achieved therapeutic serum levels of ethambutol only after the administration of high doses (25 mg/kg). In both of these patients ethambutol was undetectable in the urine 12 h later. This contrasts with the persistence of ethambutol in the urine of normal subjects for 60 to 72 h after ingestion. One patient studied
576
by Wasson and Harris (5) had a serum level below 1 ju,g/ ml 2 and 4 h after a dose of 13.6 mg/kg. Rifampin participates in an enterohepatic circulation. This drug appeared early in the blood of one of our patients but then rapidly disappeared, suggesting that proximal absorption had occurred normally but the drug had been lost after biliary excretion. Streptomycin given parenterally is excreted by the kidneys. One patient had normal renal function and was given 15 m g / k g • day. Another patient h a d undergone unilateral nephrectomy and was stabilized on a dosage of 15 m g / k g • 36 h. Both patients had elevated blood levels (46 and 52 u g / m l ; usual therapeutic range, 10 to 40), and both developed mild vestibular toxicity that cleared after therapy stopped. Our patients who were treated with isoniazid and ethambutol together or in combination for brief periods with streptomycin improved clinically and radiographically. Conventional therapy with these oral agents thus seems to be adequate, but measurement of serum levels is necessary if one is to document adequate intestinal absorption. If one plans to use rifampin, measurement of the postabsorptive blood levels is essential. A C K N O W L E D G M E N T S : The authors thank J. Kenneth McKlatchey, Ph.D., for measuring the antituberculous drug levels at National Jewish Hospital and Research Center, Denver, Colorado; and John A. Pierce, M.D., for helpful guidance. Grant support: in part by Grant # R R 00036 from the National Institutes of Health, Bethesda, Maryland. Received 6 December 1976; revision accepted 18 July 1977. • Requests for reprints should be addressed to Robert M. Bruce, M.D.; Pulmonary Division, Washington University, 660 South Euclid Ave.; St. Louis, MO 63110.
References 1. W I S E L: Iatrogenic short bowel syndrome: surgical treatment of morbid exogenous obesity. Pract Surg 2:176-214, 1975 2. W I L L S CE JR: Jejuno-ileostomy for obesity. J Med Assoc Ga 58:456-461, 1969 3. W I L L S CE J R : Tuberculosis after jejunoileal bypass (letter). JAMA 235:1425, 1976 4. P I C K L E M A N JR, E V A N S LS, K A N E JM, F R E E A R K RJ: Tuberculosis after
jejunoileal bypass for obesity. JAMA 22>A:1AA, 1975 5. WASSON KR, HARRIS JO: The treatment of tuberculosis (TB) in the presence of malabsorption syndromes (MAS). (Abstract) Am Rev Resp Dis 113:51, 1976 6. BATTERSHILL JH: Tuberculosis after intestinal bypass surgery for obesity (letter). Chest 70:318, 1976 7. L A W DK, D U D R I C K SJ, ABDOU NI: The effects of protein calorie malnutrition on immune competence of the surgical patient. Surg Gynecol Obstet 139:257-266, 1974 8. BISTRIAN BR, BLACKBURN G L , SCRIMSHAW NS, F L A T T J-P: Cellular
immunity in semistarved states in hospitalized adults. Am J Clin Nutr 28:1148-1155, 1975 9. H A R L A N D PSEG: Tuberculin reactions in malnourished children. Lancet 2:719-721, 1965
November 1977 • Annals of Internal Medicine • Volume 87 • Number 5
Downloaded From: https://annals.org/ by a La Trobe University User on 08/03/2018
