TB OR SLE? A DILEMMA

CASE REPORT

TUBERCULOSIS OR SYSTEMIC ERYTHEMATOSUS? A DIAGNOSTIC AND THERAPEUTIC DILEMMA

Asmah Mohd1, Emily ML Goh1, Sook-Khuan Chow1, Lai-Meng Looi2 and Swan-Sim Yeap1

Departments of Medicine1 and Pathology2, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Abstract. The diagnosis of patients with fever of unknown origin (FUO) is often problematic be- cause the range of possible differential diagnoses is broad. We report on a case in which a patient presented with FUO and was subsequently found to have both a collagen vascular disease and an intercurrent infection. Treatment for the collagen vascular disease with exacerbated the intercurrent infection. The problems in the diagnosis and management of such cases are dis- cussed.

Fever of unknown origin (FUO) has been which was not associated with chills, rigors or defined as a temperature of higher than 38.3¼C night sweats. The patient complained of a loss of (recorded repeatedly) that persists for more than appetite, weight loss, recurrent lower abdominal three weeks and that remains undiagnosed despite pain with frequent loose stools. Stools were not one week of inpatient investigations (Petersdorf accompanied by passing out of mucous or bleed- and Beeson, 1961). Making a diagnosis in such ing per rectum. There was no vomiting. Subse- cases remains a challenge as the possibilities are quently, the patient developed painless bilateral numerous. Infections are the commonest cause ankle swelling. of FUO, accounting for 22.5-40% of cases; other He had no significant past medical history common causes are collagen vascular diseases and systemic enquiry was otherwise normal. His (13-21.5%) and neoplasms (7-31%) (Gelfund and grandfather had a history of pulmonary tubercu- Dinarello, 1998). Treatment of such patients is losis. He was a non-smoker, did not drink alco- also difficult as patients with collagen vascular hol and denied any history of unprotected sexual diseases require immunosuppression, which can intercourse. exacerbate occult infections. On physical examination, the patient was We report on a case in which a patient pre- cachectic and dehydrated. He opened his eyes sented with FUO and was subsequently found to spontaneously but was confused and unable to have both a collagen vascular disease and an in- obey commands. He was febrile, 38¼C. He was tercurrent infection. The problems in the diagno- pale but free of jaundice and clubbing; there was sis and management of such cases are discussed. no lymphadenopathy. Old vasculitic lesions over Mr SM, an 18-year-old Indian tile cleaner, his palms, soles and digits were noted. On fundo- presented on the 17th May 2000 with a 6-month scopy, cytoid bodies were seen bilaterally. He had history of progressive weakness and lethargy that oral candidiasis. There was bilateral pitting ankle was associated with myalgia and generalized body edema. Cardiovascular, respiratory and abdomi- pain. He also had an intermittent low grade fever nal examinations were normal. There was no evi- dence of arthritis, rashes, alopecia or oral ulcers. Correspondence: Dr SS Yeap, Department of Medicine, Investigations yielded the following results: Faculty of Medicine, University of Malaya, 50603 hemoglobin 6.5 g/dl, MCV 76 fl, MCH 25.4 pg, Kuala Lumpur, Malaysia. white cell count (WCC) 6.5 x109/l (neutrophils Tel: 603 7950 2867; Fax: 603 7955 7740 81% and lymphocytes 11%), platelets 281x109/l,

Vol 34 No. 2 June 2003 361 SOUTHEAST ASIAN J TROP MED PUBLIC HEALTH erythrocyte sedimentation rate (ESR) 76 mm/hr, daily) followed by oral prednisolone (40 mg). His serum albumin 18 g/l [normal range (NR) 35-50], esophageal candidiasis was treated with oral alkaline phosphatase 445 IU/l (NR 30-300), ala- fluconazole (400 mg daily). nine aminotransferase (ALT) 126 IU/l (NR 5-35), His general condition improved and his fe- aspartate aminotransferase (AST) 116 IU/l (NR ver settled after a few days. However, five days 5-35), gamma-glutamyl transpeptidase (γGT) 883 later, his fever recurred. On this occasion, it was IU/l (NR 11-51), total bilirubin 4 µmol/l (NR 3- associated with a productive cough and pain and 17), total cholesterol 5.9 mmol/l (NR 3.6-5.2), swelling of his left ankle and knee. The patient triglycerides 3.5 mmol/l (NR 0.4-1.5), 24-hour had not been in contact with patients urinary protein excretion 3.19 g/dl (NR < 0.5), while he had been in hospital. On examination, serum iron 5.2 µmol/l (NR 9.5-29.9), ferritin he had shotty right anterior cervical lymphaden- 895.2 µg/l (NR 22-322), normal coagulation pro- opathy and coarse crepitations in the lower zone file, complement (C) 3 30 mg/dl (NR 86-184), of the right lung. A repeat chest X-ray showed C4 <10 mg/dl (NR 20-59), anti-nuclear antibody clear lung fields. His left knee and ankle were (ANA) positive 1:320, double-stranded DNA swollen and tender on palpation. 1,893 (NR < 200), IgG 2,040 mg/dl, (NR 931- Aspiration of the left knee recovered blood- 1,916), IgA 438 mg/dl (NR 70-473), IgM 125 mg/ stained synovial fluid with RBC 5,680, WCC 600 dl (NR 34-265). His peripheral blood film showed (polymorphs 80%, lymphocytes 20%); no organ- dimorphic red blood cells. Viral hepatitis sero- isms or crystals were seen. His blood WCC had logy was negative. Fecal occult blood tests were risen to 20x109/l and the CRP was also elevated negative. Urine microscopy showed urine RBC (14.4 mg/dl). No bacterial organisms were cul- 102/µl (NR 0-1), urine WBC 37/µl (NR 0-3) but tured from blood, sputum, or urine; fungal blood no casts or bacteria. Blood, urine and stool cul- cultures were also negative. A repeat abdominal tures were negative. The Weil-Felix test for ty- ultrasound showed no abnormality. However, a phus and the Widal test for Salmonella typhi and repeat echocardiogram showed a small pericar- S. paratyphi were negative. Sputum culture dial effusion. A further chest X-ray (21st June) showed Acinetobacter species. Sputum for acid- showed mild reticular changes which became fast bacilli (AFB) was negative. He was negative more marked after one week. On the 24th June, for HIV-1 antibody. The C-reactive protein (CRP) two samples of sputum were positive for AFB. on admission was <0.8 mg/dl (NR 0.0-0.8). Chest x-ray was normal. Upper gastrointes- He was started on anti-tuberculosis drug tinal endoscopy showed esophageal candidiasis therapy: 1g daily, ofloxacin 400 mg with no peptic ulcer disease; abdominal ultra- daily, and clarithromycin 500 mg daily, due to sound was normal. An echocardiogram showed his liver impairment. At the same time, a broad- normal left ventricular function and no vegeta- spectrum antibiotic (imipenam) was given as he tions. remained unwell and febrile. His oral predniso- lone was switched to a small dose of IV hydro- Because of the significant proteinuria and cortisone for adrenal support. active urine sediments, a renal biopsy was per- formed on the 8th June 2000; active diffuse pro- Despite all these measures, his condition liferative lupus nephritis (WHO Class IV) with failed to improve. He continued to have a spik- segmental glomerulitis was reported and marked ing temperature and required ventilatory support tubulointerstitial and vasculopathy on the 25th June 2000. He then developed dissemi- were also found. A diagnosis of systemic lupus nated intravascular coagulopathy and went into erythematosus (SLE) with renal and skin involve- acute hepato-renal failure despite all supportive ment was made. measures. The patient died on the 27th June 2000. The patient was started on intravenous ampi- Autopsy showed disseminated TB in the lungs, cillin-sulbactam for his Acinetobacter infection; kidneys, liver and spleen. for his lupus nephritis, he was given three days This patient illustrates the diagnostic diffi- of intravenous (IV) methylprednisolone (500 mg culties in FUO. His initial presenting problems

362 Vol 34 No. 2 June 2003 TB OR SLE? A DILEMMA were non-specific, with abdominal symptoms as diagnosis of collagen vascular diseases is gener- well as fever. The fever, alopecia, proteinuria and ally useful, but it is known that chronic infections later the immunological tests, suggested a diag- such as TB can also give rise to elevated autoan- nosis of SLE. However, SLE is much more com- tibody levels. Up to 40% of TB patients can have mon in females and our patient was male. Fever a positive ANA. However, antibodies to double- and weight loss could also be due to TB, espe- stranded DNA are said to occur rarely (< 5%) in cially in a country endemic for TB, such as Ma- patients with TB (Adebajo and Isenberg, 1995). laysia. It has been estimated that the prevalence Our patient’s markedly elevated double-stranded of TB in Southeast Asia is 524 per 100,000, which DNA titer was probably due to his SLE. The is the highest of any region of the world (Dye et American College of Rheumatology has pub- al, 1999). Infections, especially extra-pulmonary lished criteria for the identification of patients TB, remain a leading cause of FUO (Gelfund and with SLE (Tan et al, 1982): a person is said to Dinarello, 1998). Therefore, in this patient, a thor- have SLE if four of the following eleven criteria ough search for TB was made when he was first are present, namely, malar rash, discoid rash, pho- admitted: all the initial investigations were nega- tosensitivity, oral ulcers, arthritis, serositis, renal tive. However, the diagnosis of extra-pulmonary disorder, neurologic disorder, hematologic disor- TB is difficult: miliary or disseminated TB can der, immunologic disorder or presence of ANA. often present with fever, night sweats, anorexia, Strictly speaking, this patient did not fulfill these weakness and weight loss without any respira- criteria for the diagnosis of SLE: he had only three tory symtoms or sign (Raviglione and O’Brien, of the eleven criteria: renal disease, positive ANA 1998). In addition, SLE patients have an increased and positive double-stranded DNA (immunologic susceptibility to infection due to many abnormali- disorder) in a high titer only. Nevertheless, based ties in their immune system, such as immunoglo- on his renal biopsy findings, we decided to treat bulin deficiency, acquired and inherited comple- him for SLE. ment deficiencies, defects in chemotaxis and ph- There is no doubt that high-dose corticos- agocytic activity and delayed and teroids, including pulsed IV methylprednisolone abnormalities of cellular immunity (Ginzler, and other immunosuppressants, are the treatment 1997). Therefore, both problems can co-exist in of choice in proliferative lupus nephritis (Austin the same patient. and Barlow, 2000). The use of corticosteroids in Several investigations for TB were unhelp- patients with TB is unclear: it has been recom- ful in this patient. The chest X-ray is frequently mended that adjunctive treatment abnormal in patients with disseminated TB be considered in patients with tuberculous men- (Raviglione and O’Brien, 1998) but this was not ingitis, pericarditis (Joint Tuberculosis Commit- the case in our patient until nearly a month after tee, 1998), or peritonitis (Alrajhi et al, 1998). he was admitted. Initial sputum samples for AFB There have been no studies to show that the use were negative; his Mantoux test was negative. It of corticosteroids increases the risk of develop- is well-known that false-negative reactions on ing new TB or reactivating old TB (Cline and PPD skin testing are common in patients with Davis, 1997). However, in the absence of effec- overwhelming TB (Raviglione and O’Brien, tive anti-tuberculosis therapy, corticosteroids en- 1998). Interestingly, a study from Malaysia sug- hance the virulence of tubercu- gested that 86% of patients with active TB had a losis (Varon and Marik, 2000). Our patient, two positive Mantoux test, and those cases with a weeks following his IV methylprednisolone, de- positive Mantoux test but no evidence of active veloped respiratory symptoms and shadowing on TB had evidence of past infection with TB. The his chest X-ray. We postulate that his pre-exist- study concluded that the Mantoux test in Malay- ing disseminated TB spread following the corti- sian patients was a sensitive but non-specific test costeroid therapy; it would be unlikely that he in the diagnosis of active TB (Yaacob and Ahmad, developed TB de novo during his four-week hos- 1990). pitalization given that he had had no obvious close The measurement of autoantibodies for the contact with TB patients.

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It has been shown that the use of prophylac- incidence, prevalence, and mortality by country. tic in SLE patients starting long-term JAMA 1999; 282: 677-86. corticosteroids in a country endemic for TB (In- Gaitonde S, Pathan E, Sule A, Mittal G, Joshi VR. dia) reduces the incidence of future TB (Gaitonde Efficacy of isoniazid prophylaxis in patients with et al, 2002). However, in this case, the use of just systemic lupus erythematosus receiving long one anti-tuberculosis drug would not have stopped term steroid treatment. Ann Rheum Dis 2002; 61: the development of disseminated TB. Another 251-3. course of action may have been to stop his oral Gelfund JA, Dinarello CA. Fever of unknown origin. prednisolone as soon as his fever recurred, shortly In: Fauci AS et al, eds. Harrison’s principles of th after the IV methylprednisolone. However, this internal medicine. 14 ed. New York: McGraw Hill, 1998: 780-5. may have led to an exacerbation of his lupus ne- phritis. Ginzler EM. Infections in systemic lupus erythemato- sus. In: Wallace DJ, Hahn BH, eds. Dubois’ lu- In conclusion, in patients with prolonged pus erythematosus. 5th ed. Williams and Wilkins, fever and an atypical presentation of connective 1997; 903-13. tissue disease, the possibility of TB should always Joint Tuberculosis Committee of the British Thoracic be borne in mind. Society. Chemotherapy and management of tu- berculosis in the United Kingdom: recommenda- tions 1998. Thorax 1998; 53: 536-48. REFERENCES Petersdorf RG, Beeson PB. Fever of unexplained ori- gin: report on 100 cases. Medicine 1961; 40: 1- Adebajo AO, Isenberg DA. Tropical rheumatology. 30. Immunological aspects. Bailliere’s Clin Rheuma- Raviglione MC, O’Brien RJ. Tuberculosis. In: Fauci tol 1995; 9: 215-29. AS et al, eds. Harrison’s principles of internal Alrajhi AA, Halim MA, al-Hokail A, et al. Corticos- medicine. 14th ed. New York: McGraw Hill, teroid treatment of peritoneal tuberculosis. Clin 1998: 1004-14. Infect Dis 1998; 27: 52-6. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised Austin HA, Balow JE. Treatment of lupus nephritis. criteria for the classification of systemic lupus Semin Nephrol 2000; 20: 265-76. erythematosus. Arthritis Rheum 1982; 25: 1271- Cline JC, Davis SM. Risks of infection or reactivation 7. of tuberculosis associated with chronic corticos- Varon J, Marik P. Corticosteroids for tuberculosis? teroid therapy. Ann Pharmacother 1997; 31: 775- Postgrad Med 2000; 107: 102-3. 6. Yaacob I, Ahmad Z. Clinical significance of Mantoux Dye C, Scheele S, Dolin P, Pathania V, Raviglione test in Malaysian patients. Med J Malaysia 1990; MC. Global burden of tuberculosis. Estimated 45: 231-4.

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