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Vol. 89, No. 1 January, 1996

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Original Contributions

5 Acute Renal Failure Associated With Use of Angiotensin Converting Enzyme Inhibitor — A Report of Two Chiidren with Down’ Syndrome

Eechampati Krishna, M.D.; Ashok V. Mehta, M.D.; Arumughakumari B. Subramanyamm, M.B.B.S.; Ahmad A. Wattad, M.D.

7 Extrapulmonary Tuberculosis in Tennessee; Lessons From the Last Decade — Thomas M. Roy, M.D.; Jay B. Mehta, M.D.; Leo M. Harvill, Ph.D.

Regular Features

13 Trauma Rounds — Open Pelvic Fracture; Delayed Diagnosis 15 Vanderbilt Morning Report — A Veteran With Eosinophilia; An Unavoidable Complication of Septic Arthritis

18 Department of Health Report — Child Fatality Review in Tennessee

19 Loss Prevention Case of the Month — Another Pediatric Nightmare

TMA Organizational

28 Highlights of the TMA Board of Trustees Meeting — October 7-8, 1995

President’s Page

21 Strength in Diversity

Editorials

22 Mellowing for 1996

23 Forget, Hell!!! An Apology, Sort of, or Rather, an . . . er. Explanation 23 Partners in Politics

Departments

24 Mail Box — Governor’s Office; Managed Care Revisited

24 In Memoriam

25 New Members 25 Personal News

25 Announcements

26 Actions of the Tennessee Board of Medical Examiners 26 PRA Recipients

30 Continuing Medical Education Opportunities

31 TMA Alliance Report — Partners in Politics

33 Placement Service

34 Information for Authors 34 Advertisers in this Issue

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JANUARY, 1996 VOL. 89, NO. 1

Acute Renal Failure Associated With Use of Angiotensin Converting

Enzyme Inhibitor —

A Report of Two Children With Down ’s Syndrome

EECHAMPATI V. KRISHNA, M.D.; ASHOK V. MEHTA, M.D.; ARUMUGHAKUMARI B. SUBRAHMANYAM, M.B.B.S.; and AHMAD A. WATTAD, M.D.

Introduction

Angiotensin converting enzyme (ACE) inhibitors are widely used in the treatment of hypertension and congestive heart failure (CHF). Rarely, they are reported to cause renal dysfunction in adults with CHF,' dehydration,^ and hyponatremia.^ In the pe- diatric population, they are reported to cause renal insufficiency in patients with renal artery stenosis"' and coarctation of the aorta,^ and in newborn in- fants.^" We describe two children with Down’s syndrome and CHF where acute renal failure was probably induced by ACE inhibitor therapy without associated renal artery stenosis or coarctation of the aorta.

Case Reports

Patient 1 is a 5-year-oId white boy with Down’s syn- drome, born with a complete atrioventricular (AV) canal. He underwent patent ductus arteriosus (PDA) ligation at 6 months of age and complete repair of the AV canal at 2 years

From the Department of Pediatrics, James H. Quillen College of Medi- cine, East Tennessee State University, Johnson City.

Supported by a grant from John,son City Medical Center Foundation. Reprint requests to Department of Pediatrics, 310 State of Franklin Road, Suite 301, Johnson City, TN 37604 (Dr. Mehta).

of age. After surgery, he had mild to moderate right CHF, mildly elevated pulmonary vascular resistance (3.4 units/sq m), and moderate tricuspid regurgitation. He was maintained on oral digoxin (10 p-g/kg/day) and hydrochlorothiazide- spironolactone (12.5 mg three times a day, 3 mg/kg/day). As his CHF worsened at 5 years of age, he was started on oral enalapril (1.25 mg twice a day, 0.2 mg/kg/day) as a trial. Additionally, he received oral furosemide 1 mg/kg once a day. At that time, his urinalysis was normal, blood urea nitro- gen (BUN) was 8 mg/dl, serum creatinine 0.5 mg/dl, serum sodium 135 mEq/L, potassium 6 mEq/L, chloride 97 mEq/L, and COj 27 mEq/L. His creatinine clearance was 100 ml/min as calculated by the Schwartz formula (normal 90 to 1 37 ml/ min). Three weeks after enalapril therapy, his BUN was 56 mg/dl but serum creatinine determination was not done. His general condition, hydration, and urine output, however, were normal, as were his vital signs, which included heart rate of 108/min, respiratory rate 30/min, and blood pressure 85/56 mm Hg. Two weeks later he had a complete heart block and a ventricular rate of 35/min, respiratory rate 28/min, and blood pressure 70/50 mm Hg. His serum digoxin level of 7.2 ng/ml was corrected by digoxin immune Fab therapy, resulting in normal sinus rhythm, but his renal function deteriorated, with a BUN of 91 mg/dl and serum creatinine of 3.2 mg/dl. At this time, his serum sodium was 125 mEq/L, potassium 7.7 mEq/L, chloride 92 mEq/L, and COj 19 mEq/L. His CBC showed a WBC count of 9,200/cu mm, with no eosinophils, and urinaly- sis showed 3 to 5 WBC/HPF. Intravenous amrinone therapy was started and his electrolytes returned to normal. Despite aggressive management, he remained anuric and died. Dialy- sis was not performed. Unfortunately, autopsy was denied.

JANUARY, 1996

Patient 2 is a 5-month-old white girl with Down’s syn- drome, born at 32 weeks gestation (birth weight 1.9 kg) with a complete AV canal, mild hypoplasia of the left ventricle, PDA, moderate AV valvar insufficiency, and hydrops fetalis. She had a prolonged neonatal hospital course, complicated by ventilatory dependency for two months and CHF. She under- went PDA ligation and pulmonary artery banding at 2 months of age. At 5 months of age, she was noted to have cyanosis at rest, significant biventricular hypertrophy, and mild to mod- erate pericardial effusion. She was transferred to a tertiary care center, where cardiac catheterization showed an end- diastolic pressure of 15 mm Hg in both ventricles and a pres- sure gradient of 80 mm Hg across pulmonary artery band. Her medications were oral digoxin (9 p,g/kg/day in tvzo divided doses), oral furosemide (4.5 mg/kg/day in two divided doses), chlorothiazide (20 mg/kg/day in two divided doses), and spironolactone (3 mg/kg/day in two divided doses) for CHF. Since her end-diastolic pressure in both ventricles was high, oral captopril was added to her regimen by the tertiary care center. The captopril dose was gradually increased to 0.25 mg three times a day (0.17 mg/kg/day) without any problems. At the time of starting captopril, she had good urine output, nor- mal urinalysis (3 to 5 WBC with no eosinophils), and normal renal function (BUN of 15 mg/dl and serum creatinine 0.4 mg/dl). As calculated by the Schwartz formula, her creatinine clearance was low at 70 ml/min. Her serum sodium was 133 mEq/L, potassium 4.7 mEq/L, chloride 96 mEq/L, and CO2 29 mEq/L. Her CBC showed a WBC count of 1 1,200/cu mm with no eosinophils. Additionally, she was started on levo- thyroxine sodium 25 p,g once a day because of hypothyroid- ism (TSH 11.5 |xU/ml and free T4 3.13 |xg). Her blood pres- sure before starting ACE inhibitors was 85/55 mm Hg, which was in the 50th percentile for her age. A week after beginning captopril therapy, she was transported back to us presumably stable and well hydrated. During transportation, she devel- oped apnea, which initially responded to bag and mask venti- lation. Upon arrival at this center, ventilatory support was started because of respiratory failure. The patient was found to be in acute renal failure, with a BUN of 80 mg/dl and serum creatinine of 4.3 mg/dl. She developed profound metabolic acidosis and subsequently progressed to asystole, not responsive to aggressive management. At autopsy, the right kidney weighed 19 gm and the left kidney weighed 16 gm, for a total weight of 35 gm (normal for the child’s size; 37 to 38 gm). Microscopic examination of the kidneys showed normal development of glomeruli and tubules but patchy nephrocalcinosis. The lungs showed bilateral bronchopneumonia and partial atelectasis of the left lung. The cardiac defects were also confirmed.

Discussion

In addition to digoxin and diuretics, ACE inhibi- tors are frequently used in the management of hy- pertension and CHF in infants, children, and adults as afterload reducing agents. They are effica- cious and well tolerated, with minimal side effects in children with or without renal disease. They re- duce blood pressure by inhibiting the enzyme peptidyl dipeptidase, thereby blocking the conver- sion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor, and is responsible for maintaining blood pressure. It maintains renal perfusion by causing constriction of the efferent glomerular arterioles.^ When ACE inhibitors are used in conditions where renal function depends on the renin-angiotensin system, such as bilateral renal

artery stenosis,"^ '"* stenosis in the artery of a solitary functioning kidney, CHF,' polycystic kidney dis- ease,'^ or coarctation of the aorta,^ they can lead to renal dysfunction by causing a drop in the renal perfusion pressure.

Both our patients had CHF and Down’s syn- drome. Our first patient, a 5-year-old child, was noted to have a high BUN of 56 mg/dl after three weeks of enalapril therapy and had renal failure af- ter five weeks of therapy. In contrast, our second child, a 5-month-old infant, developed acute renal failure after one week of captopril therapy. ACE inhibitor-induced renal failure is known in adult lit- erature*'^’^''' but has not been emphasized in pedi- atric literature. There are very few reports of ACE inhibitor-induced renal dysfunction in children.''” Rosa et al" reported seven cases of neonatal anuria with maternal use of ACE inhibitors during preg- nancy. The other pediatric reports describe renal in- sufficiency in premature infants, newborns, and in- fants less than 4 months of age.''"'" Since ACE inhibitors are cleared primarily by renal elimina- tion, and the kidneys are not fully mature in prema- ture infants and neonates, they may cause prolonged hypotension, resulting in renal dysfunction in this age group.'" Our patient 2 had a borderline low creatinine clearance at the beginning of ACE inhibitor therapy. It is not known to what extent this contributed to her renal dysfunction. However, she had no episodes of hypotension and was not receiv- ing large doses of ACE inhibitors. Neither of our patients had evidence of interstitial nephritis as a cause of renal dysfunction, such as fever, rash, eosinophilia, or eosinophiluria.’^ No nephrotoxic drugs were used in our patients in the month prior to starting ACE inhibitor therapy. Neither of them had any clinical evidence of sepsis or overwhelming infections.

In adults, the principal risk factors for renal fail- ure are thought to be hyponatremia, hypotension, volume depletion, and large doses of the ACE in- hibitor.^ Hyponatremia, an indicator of maximal ac- tivation of the renin-angiotensin-aldosterone axis, is considered the most useful marker for renal insuffi- ciency in the adult population.^ Both of our patients had a low normal serum sodium at the beginning of the ACE inhibitor therapy. Both were receiving sig- nificant doses of diuretics during ACE inhibitor therapy, which may have accentuated the borderline serum sodium and the impaired auto-regulation of the renin-angiotensin system, resulting in the low serum sodium in our first child. When heart block occurred in our first child, he had both hypona- tremia and hypotension, which may have contrib-

JOURNAL OFTHE TENNESSEE MEDICAL ASSOCIATION

uted to renal failure. Children with CHF who are receiving salt-restricted diet and diuretics should be carefully monitored for development of hypo- natremia or hypovolemia during ACE inhibitor therapy. Concurrent use of potassium-sparing di- uretics should be avoided because it may cause hyperkalemia. Parents should be alerted about the increased risk of adverse effects to the kidney if the child becomes dehydrated. In these situations, it may be necessary to reduce the doses of diuretics and ACE inhibitors and may be necessary to give parenteral fluid. Even though both of our patients died, renal failure due to ACE inhibitor therapy can be reversible in some cases.

Various renal abnormalities, including obstruc- tive uropathy, renal hypoplasia and dysplasia, nodu- lar renal blastema, and cystic malformation of col- lecting tubules with immature glomeruli, have been reported in children with Down’s syndrome.'® Nei- ther of our children with Down’s syndrome had any preexisting renal disease. Both of our patients had normal urinalysis, and normal BUN and serum crea- tinine prior to ACE inhibitor therapy. Our second child had a normal gross and microscopic examina- tion of both kidneys also. Naeye"" has reported that newborns with Down’s syndrome have 60% fewer glomeruli than normal newborns. Renal hypoplasia can cause tubular insufficiency and defective uri- nary concentration. An association between ACE inhibitor therapy and acute renal dysfunction has been noted in other bilateral renal diseases, e.g., polycystic kidney,'® bilateral renal artery stenosis, and scleroderma.'"' Leversha et aP reported renal failure in 8 of the 63 infants who were treated with enalapril for CHF. Three of these infants had Down’s syndrome, complete AV canal, and CHF, and died after developing renal failure. We suggest that

caution should be exercised when using ACE in- hibitors in children with Down’s syndrome and CHF.

Conclusions

From our experience and that of others®'" we recommend that the principal risk group for renal failure after ACE inhibitor therapy should include neonates, infants, and children with Down’s syn- drome and CHF. Additionally, these children should be monitored carefully for urine output, hypo- volemia, hyponatremia, and renal failure by periodic measurement of BUN and serum creatinine. □

REFERENCES

1. Ljungman S. Kjekshus J. Swedberg K: Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) Trial). Am J Cardiol 70:479-487, 1992.

2. Bridoux F, Hazzan M. Fallot JL, et al: Acute renal failure after the use of angio- tensin-converting-enzyme inhibitors in patients without renal artery stenosis. Nephrol Dial Transplant 7:100-104, 1992.

3. Packer M. Lee WH, Kessler PD, et al: Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure. Am J Cardiol 10:837-844, 1987.

4. Colavila RD, Gaudio KM, Siegel NJ: Reversible reduction in renal function during treatment with captopril. Pediatrics 71:839-840, 1983.

5. Wood EG, Bunchman TE, Lynch RE: Captopril-induced reversible acute renal failure in an infant with coarctation of the aorta. Pediatrics 88:816-818, 1991.

6. Wells TG, Bunchman TE, Kearns GL: Treatment of neonatal hypertension with enalaprilat. J Pediatr 117:664-667, 1990.

7. Leversha AM. Wilson NJ. Clarkson PM, et al: Efficacy and dosage of enalapril in congenital and acquired heart disease. Arch Dis Child 70:35-39, 1994.

8. Scammell AMN, Arnold R, Wilkinson JL: Captopril in treatment of infant heart failure: a preliminary report. Int J Cardiol 16:295-301, 1987.

9. Shaw NJ, Wilson N, Dickinson DF: Captopril in heart failure secondary to a left to right shunt. Arch Dis Child 63:360-363. 1988.

10. Tack ED, Perlman JM: Renal failure in sick hyperten.sive premature infants receiving captopril therapy. J Pediatr 112:805-810, 1988.

11. Rosa FW, Bosco LA. Graham CF. et al: Neonatal anuria with maternal angio- tensin converting enzyme inhibition. Obstet Gynecol 74:'i7\-‘i74, 1989.

12. Lloyd TR. Mahoney LT. Knoedel D, et al: Orally administered enalapril for infants with congestive heart failure: a dose-finding study. J Pediatr 114:650-654, 1989.

13. Steinman TI, Silva P: Acute renal failure, skin rash, and eosinophilia associated with captopril therapy. Am J Med 75:154-156, 1983.

14. Kalra PA, Mamtora H, Holmes AM, et al: Renovascular disease and renal complications of angiotensin-converting-enzyme inhibitor therapy. Quart J Med 77:1013-1018, 1990.

15. Chapman AB, Gabow PA, Schrier RW: Reversible renal failure with ACE inhibitors in polycystic kidney disease. Ann Intern Med 115:769-773, 1991.

16. Ariel I. Wells TR. Landing BH. ct al: The urinary system in Down syndrome: a study of 124 autopsy cases. Pediatr Pathol 11:879-888, 1991.

17. Naeye RL: Prenatal organ and cellular growth with various chromosomal disor- ders. Biol Neonat 11:248-260, 1967.

HELP FOR IMPAIRED PHYSICIANS

The Tennessee Medical Foundation Impaired Physician Peer Review Committee as- sists doctors who are suffering from the disease of chemical dependence, or mental or emotional illness, or both, including certain behaviors problematic for physicians. The thrust of the program is rehabilitative, not punitive. The Committee is composed of physicians who have special expertise in these areas, some from personal experience. Effective treatment for these illnesses is achieved most easily when the disease or illness is detected early. The Committee urges family, friends, and associates to avoid misguided sympathy which enables a physician’s impaired condition to deteriorate.

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Call the TMF Impaired Physician Program at (615) 893-7755 in Murfreesboro. Tele- phone message service available around the clock.

JANUARY, 1996

Extrapulmonary Tuberculosis

In Tennessee:

Lessons from the Last Decade

THOMAS M. ROY, M.D.; JAY B. MEHTA, M.D.; and LEO M. HARVILL, Ph.D.

Introduction

After half a century of consistent decline, the in- cidence of tuberculosis (TB) in the United States increased in 1986. This resurgence finally ended in 1993, as the Centers for Disease Control (CDC) re- ported a decline in the total number of active TB cases in the nation. Ironically, in Tennessee this number rose from 527 in 1992 to 555 in 1993.

A previous review of extrapulmonary TB in Ten- nessee documented an incidence that was below the national average.' A relative increase in the per- centage of extrapulmonary cases was observed but could be explained by a stable number of extra- pulmonary cases with a declining number of pulmo- nary cases. As might be expected, this has led to a higher percentage of extrapulmonary cases.

When comparing pre-acquired immunodefi- ciency syndrome (AIDS) era to post-AIDS era changes in the United States, Tennessee showed no increase in the percentage of extrapulmonary TB cases. 2 Comparing the five-year period of 1977- 1981 to 1982-1986, in Tennessee extrapulmonary TB remained at 11.3% of the total cases while in the United States it increased from 14.6% to 16.6% during the same period. The present study is an ex- tension of the statistical analysis comparing the in- cidence of extrapulmonary TB in Tennessee during 1982-1986 to that of 1987-1991.

Methods

We reviewed the statistical records and annual re- ports of all TB cases in Tennessee from 1987-1991. Data were collected from the available records of

From the Divi.sion of Pulmonary Medicine (Dr. Roy), Divi.sion of Pre- ventive Medicine (Dr. Mehta), and Section of Medical Education (Dr, Harvill), James H. Quillen College of Medicine, East Tennes.see State Uni- versity, Johnson City, and the Mountain Home Veterans Affairs Medical Center.

Reprint requests to Internal Medicine, Box 70622 James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0622 (Dr. Mehta).

the Tennessee Department of Health (TDH), Divi- sion of Tuberculosis Control in Nashville.^ Similar statistics for the United States were obtained from the CDC.

All reported cases had to meet state and national definitions for TB, i.e., positive smear or culture, consistent clinical picture, and favorable response to anti-TB therapy.

During the period of 1987-1991, there were 120,432 TB cases in the United States; 21,767 of these were extrapulmonary. In Tennessee, there were 3,002 TB cases during the same five-year pe- riod, 461 of which were extrapulmonary.

We further studied extrapulmonary TB cases by site of disease and the percentage of change in the trend of TB cases with either human immunodefi- ciency virus (HlV)-positive status or outright AIDS. We compared these findings to our previous data where we had published the statistics of extrapul- monary TB in Tennessee from 1977-1981.' We ob- tained similar statistics for the United States and compared them with the state of Tennessee data. Comparison of proportions was made using chi- square tests of independence. P value was calcu- lated to determine statistical significance.

Results

Since the data from each five-year period were similar in terms of classification by anatomic site, symptoms, patient race and age, the data for all five years were pooled for further analysis.

Extrapulmonary TB in Tennessee declined from

12.0 (per 100,000 population) in 1987 to 10.7 per

100.000 in 1992. However, the U.S. rate increased from 9.3 to 10.5 during the same period.

Out of the 3,002 total TB cases in Tennessee from 1987-1991, 461 (15.4%) were extrapulmoary (Fig. 1). This delayed increase in the percentage of extrapulmonary TB in Tennessee from 11.3% to 15.4% was statistically significant (P<0.00001).

JOURNAL OF THE TENNESSEE MEDICAL ASSOCIATION

u.s.

Tennessee

20% '

150.000 -

125.000 -

100.000 -

25.000 -

20.000 -

15.000 -

10.000 - 5,000 -

1977-61 1982-86 1987-91

Total Cases of Tuberculosis and Number of Extrapulmonary Cases in the U.S. in 1977-81, 1982-06, and 1987-91

Total Cases of Tuberculosis and Number of Extrapulmonary Cases in Tennessee 1977-81. 1982-86. and 1987-91

Figure 1. Percentages of change in extrapulmonary TB - United States vs. Tennessee.

When the data were placed in a graph (Fig. 2), it was clear that the percentage of extrapulmonary TB cases in Tennessee fluctuated very little for the first ten years, and then increased significantly. During the period (1977-1986), the U.S. data showed an increase in the proportion of extrapulmonary TB from 14.6% in the first five years (1977-1981) to 16.6% in the next five years (1982-1986), which was statistically significant (P<0.0001). In the state of Tennessee, 11.3% of the total TB cases were extrapulmonary for the period, which remained un- changed from 1977-1981 and 1982-1986.

As the number of AIDS cases in Tennessee has increased, the number of TB and AIDS (co-morbid- ity) cases has also risen. Between 1991-1993, 80 AIDS cases with concomitant TB were reported for the state. Of these, 17 (21.2%) had extrapulmonary TB — an increase from the 15.6% recorded for Ten- nessee for the period 1987-1991 (Table 1).

Thus, an increase in co-morbidity of AIDS and TB was noted in the last five years — a rather late phenomenon compared to the national statistics. Similarly, an increase in the percentage of extra- pulmonary TB in Tennessee was delayed when compared to the national trend (Fig. 1).

Discussion

During the last few years, the proportion or per- centage of extrapulmonary TB cases in Tennessee has been increasing (Fig. 2). Most of these cases involve pleural or lymphatic TB. The epidemiologic pattern of this increase in extrapulmonary TB in Tennessee has followed the national trend with a lag time of about four or five years, a delay similar to that noticed in the AIDS epidemic. The number of AIDS cases started to rise in Tennessee a few years after the full impact of the AIDS epidemic was appreciated in the United States in 1981-1985. Similar “delayed effect” was noticed in an epidemic of viral hepatitis in West Tennessee.'*

-1 1 1 1 1 1 1 1 1 I I I I i i t i

1977 1978 1979 1980 1981 1982 1983 1984 1985 1985 1987 1988 1989 1990 1991 1992

Extra-pulm. TB Total TB Extra-pulm. TB as y->o1 Total

1977-1981

455

4023

11.3%

1962-1966

356

3149

11.3%

1987-1991

461

3002

15.4%

Figure 2. Percentages of extrapulmonary TB in Tennessee, 1977- 1991.

From our study, it appears that changes in na- tional trends for TB and other communicable dis- eases can be taken as reliable indicators of what lies ahead for Tennessee. Such awareness would allow appropriate reallocation of public health resources and should assist health departments in implement- ing corresponding program modifications in order to meet the challenges in a timely fashion.

Despite a decrease in the total number of cases of TB in Tennessee, our state ranks tenth in the nation for reportable cases (10.7 per 100,000 popu- lation in 1992). The actual number of individuals with extrapulmonary expression of this potentially fatal infection has increased during the last decade.

In 1983, the diagnosis of extrapulmonary TB was generally based on finding epithelioid cell granulo- mas on histologic examination of tissue or AFB on smear or culture. In special cases, the diagnosis was that of exclusion based on a patient’s clinical re- sponse to antitubercular therapy. Approximately 80% of cases of extrapulmonary TB were smear- or culture-positive. In 1992, the cases included for analysis showed a comparable rate of bacterial con- firmation at 81%. The implication is, of course, that the number of persons diagnosed with extrapul- monary TB is real and not an effect of applying different inclusion criteria.

From 1977-1986, the U.S. data showed an in- crease in the proportion of extrapulmonary TB cases from 14.6% in the first five years (1977-1981) to 16.6% in the next five years (1982-1986), which was statistically significant (P<0.0001). In the state of Tennessee, however, only 11.3% of the total TB cases reported for that interval were extrapul- monary. This percentage remained unchanged from 1977-1981 to 1982-1986.'

JANUARY, 1996

lAIWULitllllllllM

TABLE 1

EXTRAPULMONARY TUBERCULOSIS BY SITE - TENNESSEE, 1983-1992

	1983	1984	1985	1986	1987	1988	1989	1990	1991	1992
Pleural	8	23	17	20	32	37	32	31	33	23
Lymphatic	14	11	8	18	9	12	17	16	17	23
Bone	9	6	5	16	13	14	13	18	8	18
Genitourinary	11	7	7	10	8	13	8	8	5	7
Miliary	6	2	4	13	3	6	5	11	7	4
Meningeal	5	2	0	8	5	4	3	2	3	2
Peritoneal	3	4	2	3	3	2	2	1	2	5
Other	7	6	15	6	6	16	14	10	12	9
All TB Cases	645	602	568	597	609	620	601	598	574	526
Extrapulmonary TB Cases	63	61	58	94	79	104	94	97	87	91
Percentage	9.8	10.1	10.2	15.7	13.0	16.8	15.6	16.2	15.2	17.3
AIDS + TB Cases	NA	NA	NA	NA	6	14	8	13	22	22

Tuberculosis of the Lymph Nodes'. Tuberculous lymphadenopathy is the most common form of extrapulmonary TB outside the thorax. In our study, 17.0% of all extrapulmonary TB cases were lym- phatic (Fig. 3). The sites most commonly affected are the cervical and supraclavicular lymph nodes, followed by the inguinal and axillary chains. In ap- proximately 80% of patients, only a single group of nodes is involved. These nodes are tender during enlargement, but eventually soften, coalesce, and become painless. Matting of the nodes is a common phenomenon secondary to periadenitis and is thought to be an important diagnostic clue in recog- nizing tuberculous lymphadenitis. Sloughing and drainage may occur in a minority of patients.^ Computerized tomography has been used to dis- tinguish cervical tuberculous lymphadenitis from lymphadenopathy due to other causes. The scan usually shows a central low density with peripheral rim enhancement that tends to be thicker and more irregular than neoplastic lymphadenopathy.^’^

An involved lymph node is typically enlarged and approachable for biopsy. Fine-needle aspiration with cytologic examination of the specimen is the initial diagnostic procedure. This approach is less expensive and less invasive than excisional node biopsy, which may require hospitalization. The presence of caseous necrosis and epithelioid cells is the most characteristic feature in aspirated smears. Acid-fast bacilli are recognized 45% of the time.* Cultures are positive for Mycobacterium tuberculo- sis in 35% to 60% of specimens.^

Miliary Tuberculosis: Recent reports indicate striking changes in the age of those developing mil- iary TB. There has been a decreased incidence in children, and an increase in older patients. In our study, 32 out of 47 cases (68.1%) of miliary TB occurred in patients above the age of 50, with only

four cases in children.^ In some of these cases, de- creased host defenses may have been a contributing factor. In addition to age, cancer, chemotherapy and/or radiation therapy for cancer, immunosup- pressive therapy, malnutrition, and chronic renal failure are causes of decreased host defenses. Un- like others,''’’^ we did not find a significant sex difference, but like others, we found that rela- tively more blacks than whites had miliary TB.

Tuberculous Meningitis: While tuberculous men- ingitis continues to be seen in children, 10 patients out of 18 (55.6%) were above the age of 50. Out of six children with meningeal TB, four were nonwhite, a finding consistent with others in the literature.*^ Meningeal TB in the elderly is frequently a diffi- cult diagnosis. “Failure to thrive” or depression as presenting symptoms may mislead the clinician from the true diagnosis of tuberculous meningitis.

Genitourinary Tuberculosis: Some reports indi- cate that genitourinary TB has declined as rapidly as pulmonary TB, and our five-year experience showed an even greater decline in genitourinary TB, the reason for which is unclear. During the five-year period of 1982-1986, 14.6% of all extra- pulmonary TB cases were genitourinary, whereas for 1987-1991, the incidence fell to 8.9%, a drastic and statistically significant decrease (F=0.0146).

Bone/Joint Tuberculosis: There were 74 patients with bone/joint TB during the period of 1987-1991, constituting 15.2% of the total extrapulmonary cases, with equal sex distribution. This is consistent with other reports in the literature.*^ While the di- agnosis of bone/joint TB has become easier with the aid of the computed axial tomography (CT) scan and magnetic resonance imaging (MRI), treat- ment often requires surgical intervention.

Pleural Tuberculosis: Thirty-four percent of all extrapulmonary TB cases during 1987-1991 were

JOURNAL OFTHE TENNESSEE MEDICAL ASSOCIATION

9.6

‘Statistically significant decline x2 = 18.7245 df = 7 p = 0.0091

Figure 3. Percentages of extrapulmonary TB by site - Tennessee, 1982-1986 vs. 1987-1991.

pleural. This form of the disease is commonly asso- ciated with pulmonary TB. Clinical presentations include pleural pain, effusion, and, rarely, empyema. Pleural fluid examinations generally show high pro- tein, high LDH, and low glucose levels. Mesothelial cells are usually absent. Lymphocytosis is fre- quently noted, but many polymorphonuclear cells may be present in the acute phase. Smears for acid- fast bacilli are rarely positive, but cultures for my- cobacteria are positive in 50% of the cases. Pleural biopsy increases the diagnostic yield.

Elderly patients with primary TB often have pleural effusion. Hence, if a nursing home resident has a pleural effusion, TB should be considered. Since primary tuberculous infection generally im- plies a recent exposure, another active or contagious case of TB should be sought in the vicinity.

Tuberculosis of Other Sites: The incidence of TB of customarily rare sites, i.e., skin, eye, and ear, seems to have increased. In our study, this fraction increased to 12.1% for the years 1987-1991 from

9.6% for the previous five-year period, though this increase was not statistically significant (P=0.1741). Such a trend has also been seen nationally, and may be due to the growing prevalence of HIV-related TB (Fig. 3).

Treatment of Extrapulmonary Tuberculosis

The treatment of extrapulmonary TB involves the same bactericidal agents used in treating pulmo- nary TB. Site of the disease appears to be less im- portant since the bacterial burden is generally smaller in extrapulmonary TB. Agents such as isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) penetrate tissues well and attain levels suffi- cient to kill the organisms. Nine months of two- drug therapy with INH and RIF, or six-month therapy with initial intensive four-drug therapy for two months, generally show success.'^ With con- comitant HIV infections, TB therapy should con- tinue for a minimum of 12 months. Directly observed therapy may be the best method to assure compliance. The response to treatment is quite favorable in 90% to 95% of cases. When treating tuberculous lympha- denitis, the clinician must recognize that tubercu- lous lymph nodes can transiently enlarge during therapy. This does not imply relapse or treatment failure, but is attributed to cellular reaction to the by-products of mycobacterial disintegration. After successful treatment, approximately 10% of patients are left with residual nodes larger than 10 mm. Ini- tial lymph node excision does not seem to improve outcome, and is reserved for diagnostic purposes and for the minority of patients with discomfort due to large nodes that are tense, fluctuant, or drain- ing.'* Tuberculosis of the bone and joints frequently requires surgical intervention.

Effect of AIDS Epidemic

The number of extrapulmonary TB cases in the United States remained fairly constant for decades until the onset of the AIDS epidemic, which brought with it a national increase in both the actual number and the percentage of extrapulmonary TB. Patients with AIDS and concurrent TB have a higher incidence of extrapulmonary involvement.'^ This accounted for the dramatic increase in the per- centage of extrapulmonary TB cases in the United States when pre-AIDS era (1977-1981) was com- pared with post-AIDS era (1982-1986) (Fig. 1).'

In Tennessee, extrapulmonary TB as the percent- age of total cases increased slightly over the years as the incidence of pulmonary TB continued to de- cline. However, comparison of the post-AIDS era with the pre-AIDS era showed no difference in the

JANUARY, 1996

percentage of extrapulmonary TB cases.' Now the trend has changed. From our current study, it is ap- parent that the percentage of extrapulmonary TB cases is increasing in both the United States and the state of Tennessee.

Tuberculosis is one of the major diseases associ- ated with HIV infection, frequently being the first opportunistic infection. It may occur even before the total T-cell count drops below 400. In 1988, extrapulmonary TB in persons known to be HIV seropositive represented 32% of the national extrapulmonary cases. In 1987, the CDC revised the definition of AIDS to recognize the coexistence of extrapulmonary TB as a diagnostic criterion. This revision of definition for the diagnosis of AIDS not only affects the clinical management, but also current procedural terminology (CPT) codes and third party payment.

The frequency of infection with TB and HIV varies by region, reflecting the degree to which the population adopts behavior that puts them at. risk for HIV infection.’ An epidemiologic association between AIDS and TB in Tennessee has been re- corded since 1988. The total number of HlV-posi- tive patients with extrapulmonary TB in Tennessee does not fully explain the dramatic increase in the percentage of extrapulmonary TB cases. Such a phenomenon of increasing number of extrapul- monary cases has been observed in other areas as well.-' Extrapulmonary TB is most often found in minorities, and tends to occur among a younger age group. Clinical signs and symptoms frequently de- pend upon the site of involvement. Unless clinicians maintain a high index of suspicion, this diagnosis is easily missed. Regardless of the exact etiology, the increasing percentage of extrapulmonary TB cases in Tennessee is a major change in the epidemiology of TB. Awareness of these changes is crucial for primary care physicians and specialists encounter- ing such cases. Increased awareness may lead to prompt diagnosis and treatment.

Summary

In conclusion, extrapulmonary TB remains a sig- nificant fraction of the total TB cases in Tennessee.

During the last few years, the percentage of extra- pulmonary TB in Tennessee has been on the in- crease. Understanding these changes in the epidemi- ology of extrapulmonary TB will help the clinician in making a prompt diagnosis, leading to appropri- ate therapy. Understanding the changing trends at the national level may aid state health departments in reorganizing disease control programs, thus, fa- cilitating the eradication of TB and other communi- cable diseases in Tennessee. □

Acknowledgments

The authors thank Dr. Kerry Gateley and the staff of the Tuberculosis Control Program, Tennessee Department of Health, Nashville, for their kind cooperation, and Ms. Tan's Whitson Tipton for technical assistance.

REFERENCES

1. Mehta JB. Dull A, Harvill L, et al: Epidemiology of extrapulmonary tuberculo- sis: a comparative analysis with pre-AIDS era. Chest 99:1134-1138, 1991.

2. Mehta JB, Kasprzyk D. Harvill LM, et al: Extrapulmonary tuberculosis in Ten- nessee from 1977-1981: a review of statistical analysis. J Tenn Med Assoc 78:271-275, 1985.

3. Gateley K: Annual Reports: 1987-1993. Division of Tuberculosis Control, Ten- nessee Department of Health and Environment, 1993, pp 2-20.

4. Communicable Disease Control Section, Tennessee Department of Health. Hepa- titis A outbreak in Shelby County. EPI-NEWS 1(2): 1-2, 1995.

5. Thompson MM, Underwood MJ, Sayers RD. et al: Peripheral tuberculous lymphadenopathy: a review of 67 cases. Br J Surg 79:763-764, 1992.

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7. Dandapal MC. Mi.schra BM, Da.sh SP, et al: Peripheral lymph node tuberculosis: