Curious case of fever of unknown origin

Abstract

A 58-year-old immunocompetent woman presented with fever and significant weight loss of 4-month duration. She had mild pallor; rest of the examination was unremarkable. Investigations revealed anaemia with raised inflammatory markers. Cultures, serologies, routine urine examination, bone marrow examination, contrast enhanced CT and two-dimensional echocardiography examination were unremarkable. An 18F-fluorodeoxyglucose positron emission tomography with CT (18F-FDG-PET/CT) scan was performed which revealed atypical heterogenous uptake in bilateral renal cortex. Subsequently, urine GeneXpert came positive for Mycobacterium tuberculosis with sensitivity to rifampicin. She responded to category 1 antitubercular therapy. The challenges in diagnosis of genitourinary tuberculosis, low sensitivity of conventional diagnostic tests and potential role of GeneXpert and 18F-FDG-PET/CT scan are discussed in this report.

Background

Infections are the most common cause for fever of unknown origin (FUO).¹ Tuberculosis (TB), particularly extra pulmonary TB (EPTB) is not an uncommon cause for FUO especially in the tropical countries.² Genitourinary TB (GUTB) is one of the common sites for EPTB, although the estimates are variable.^{3 4} It encompasses disease caused by Mycobacterium tuberculosis at sites including the urinary tract, male and female genitalia. The clinical presentation is insidious, often without specific symptoms and atypical presentation.^{4 5} Culture has been the gold standard for diagnosis. Conventionally, three early morning urine samples have been used for culture; however, the low sensitivity, long time to positivity and possibility for false-positive result limit its utility as a diagnostic test.⁴ The newer diagnostic tools such as nucleic acid amplification tests (NAATs) are still under evaluation.⁶ Given this lacuna, the imaging techniques like intravenous urography and abdominal CT scans play an important role in diagnosis.⁷ The non-specific presentation and low sensitivity of the definitive diagnostic test may lead to delayed diagnosis and treatment, and ensuing complications.

The diagnostic armamentarium in FUO has been strengthened by the addition of 18F-fluorodeoxyglucose positron emission tomography with CT (18F-FDG-PET/CT) scan, while other modalities like whole-body MRI are still under evaluation.^{8 9} The role of 18F-FDG-PET/CT is limited in genitourinary lesions due to physiological tracer excretion.¹⁰ Its utility in renal involvement of TB is not well studied.¹¹ We present a case of FUO diagnosed to have renal TB initially suspected on the basis of unusual findings on a 18F-FDG-PET/CT scan, and subsequently confirmed by GeneXpert.

Case presentation

A 58-year-old woman presented with continuous high grade fever (38.6°C±0.2°C) of 4-month duration associated with generalised weakness and malaise. No other localising symptoms were present. There was no significant history. She did not have pets at home but had history of intake of unpasteurized milk for 30 years. She was evaluated at a local hospital; however, the aetiology of fever remained elusive. She was referred to our institute for further evaluation and management.

At presentation, she was febrile (38.8°C) with stable vitals. Pallor was present; rest of the general and systemic examination was essentially normal. Initial blood investigations revealed normocytic, normochromic anaemia with reversal of albumin: globulin ratio, high erythrocyte sedimentation rate and increased serum alkaline phosphatase levels (table 1). Her blood as well as urine cultures (both bacterial and fungal) was sterile. Workup for typhoid, malaria, leishmaniasis, dengue, scrub typhus, leptospirosis and histoplasmosis was negative. Immunoglobulins for brucella (IgG and IgM), and antinuclear antibody were negative. A contrast enhanced CT of chest and abdomen did not reveal any nodules or lymphadenopathy. Bone marrow examination was not suggestive of atypical cells or parasites. Two-dimensional echocardiography was normal. An 18F-FDG-PET/CT scan revealed atypical heterogenous uptake in bilateral renal cortex. A repeat ultrasonogram and MRI of abdomen did not reveal any renal or hepatic abnormality (figure 1). Urine routine examination showed no pyuria; however, with the suspicion of renal TB on 18F-FDG-PET/CT scan image findings, three early morning urine samples were sent for acid-fast bacilli stain along with GeneXpert and liquid culture for urine. The GeneXpert result was positive and sensitive to rifampicin (table 2). Patient was started on category 1 antitubercular therapy, her fever spikes subsided and was discharged to follow-up on outpatient basis.

Table 1.

Routine haematological and biochemical profile

	Prior to admission	At admission	At discharge
Hb (g/dL)	6.8	7.6	7.8
TLC (/mm3)	8800	5580	8600
Platelet count (/mm3)	432×106	558×106	547×106
Differential leucocyte count	N 84%, L 10%	N 85%, L 7.2%	N 82%, L 11%
Urea (mg/dL)	34	26	52
Creatinine (mg/dL)	1.2	1.2	1.1
Calcium (mg/dL)	8.4	8.1	8.2
Phosphate (mg/dL)	3.8	3.5	4.4
Sodium (mEq/L)	141	131	132
Potassium (mEq/L)	4.2	4	4.1
Bilirubin (mg/dL)	0.8	0.2	0.3
Total protein (g/dL)	6.9	6.7	7.6
Albumin/globulin	2.5/4.4	2.4/4.3	2.8/4.8
AST (IU/L)	47	23	11
ALT (IU/L)	62	16	5
ALP (IU/L)	782	840	430
ESR (mm 1st hour)	64		32

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ESR, erythrocyte sedimentation rate; Hb, haemoglobin; L, lymphocyte, N, neutrophil; TLC, total leucocyte count.

Figure 1.

(A) Maximum intensity projection, (B) coronal fused and (D) transaxial fused positron emission tomography/CT image shows a diffusely increased cortical accumulation of FDG in both kidneys with negligible pelvicalyceal retention. No other site of metabolically active disease was localised. (C) MRI of abdomen and (E) intravenous pyelography did not reveal any renal abnormality.

Table 2.

Results of urine examinations

	Sample 1	Sample 2	Sample 3
RBC	Nil	2–4/hpf	0–1/hpf
WBC	5–6/hpf	4–6/hpf	1–2/hpf
Casts	Nil	Nil	Nil
Protein	Trace	Trace	Trace
Sugar	Nil	Nil	Nil
AFB stain	Negative	Negative	Negative
GeneXpert	Positive	–	Positive

AFB, acid-fast bacilli; hpf, high power field; RBC, red blood cells; WBC, white blood cells.

Differential diagnosis

Initial differentials of chronic infectious diseases like brucellosis, visceral leishmaniasis and histoplasmosis; lymphoreticular malignancy and connective tissue disease like systemic lupus erythematosus were kept and the relevant investigations were done.

Treatment

Patient was started on category 1 antitubercular regimen.

Outcome and follow-up

Patient was followed up at 4 months after discharge; she is afebrile, gaining weight and asymptomatic.

Discussion

The patient presented with 4-month history of fever without localisation and based on suspicion on 18F-FDG-PET/CT scan, a urine GeneXpert examination was done which confirmed the diagnosis of GUTB. Interestingly, she had no features of lower urinary tract symptoms.

The clinical presentation of GUTB is varied depending on the part/parts affected. There may be a wide variety of symptoms, the most common being irritative voiding symptoms like frequency, urgency, dysuria and haematuria; however, it may present with non-specific symptoms or localising symptoms may appear late in the disease course.⁴ Renal involvement of TB may manifest early only with biochemical abnormalities including proteinuria, pyuria, isolated haematuria or impairment of kidney function. Irritative symptoms manifest when the disease involves the ureters and bladder.¹² Classically, irritative voiding symptoms with sterile pyuria are considered the hallmark of GUTB; however, these features may not be present in the absence of lower urinary tract involvement as seen in the present case. Thus, GUTB should be considered as a differential diagnosis in the evaluation of FUO even in the absence of these classically described features, particularly in high-burden settings.

GUTB is usually suspected in patients with fever and symptoms suggestive of lower urinary tract infection wherein urine examination reveals persistent pyuria and cultures are sterile. The various abnormalities described in routine urine examination includes pyuria, haematuria and proteinuria. The gold standard for the diagnosis of GUTB is culture of M. tuberculosis from urine sample. Three early morning urine samples are sent for culture and the reported sensitivity varies from 10% to 80% depending on the disease severity and the definitions used.⁴ The large variation in reported sensitivity, long turnaround time and possibility of false-positive results in cultures due to the presence of M. smegmatis limit its utility as a diagnostic test. Molecular diagnostic tests employing rapid NAATs are useful in various forms of extrapulmonary TB as it increases yield in these paucibacillary diseases. The Xpert Mycobacterium tuberculosis /Rifampicin (MTB/RIF) is an automated, heminested real-time PCR for detecting MTB complex along with mutation that confers rifampicin resistance using three specific primers and five molecular probes to ensure a high degree of specificity. The advantages of being a simple test with high sensitivity and specificity, turnaround time of only 2 hours and no special laboratory requirements have led to its increased use in the last few years. It has been recommended in various forms of EPTB; however, more data are required in GUTB before it can be recommended for routine use in this form of EPTB.^{6 13} In the present case, routine examination of urine did not give any clue; however, the diagnosis was confirmed by a urine GeneXpert test.

Radiological findings in GUTB depend on stage of the disease. The challenge lies in the detection of subtle early changes before irreversible anatomical changes have occurred. Intravenous urography is a useful test; however, 10%–15% of patients with active renal TB may have normal findings, particularly in the setting where there is isolated renal parenchyma involvement sparing the calyces.^{14 15} The earliest changes in kidneys in GUTB are the formation of granulomas of ≤3 mm in the renal parenchyma and papillary necrosis; both CT scan and MRI are highly sensitive investigations to detect early changes.¹⁵ It is intriguing that both CT and MRI revealed normal anatomy of kidneys in the present case, whereas the 18F-FDG-PET/CT scan revealed atypical heterogenous uptake in bilateral renal cortex. Probably, the very small isolated renal parenchyma granulomas were not picked up by the CT and MRI scans. A similar case with uptake in bilateral kidneys due to TB has been reported previously.¹⁶ Renal TB being result of haematogenous dissemination, bilateral kidney involvement in TB has been reported in about 13% of the cases.¹⁷ The present case had bilateral uptake on the 18F-FDG-PET/CT scan.

The role of biopsy is limited in the diagnosis of renal TB. The classical presentation involving the urinary collecting system is usually diagnosed on microbiological and radiological investigations. Isolated renal parenchyma involvement, including interstitial nephritis and glomerulonephritis, is uncommon, and there is sparse literature on the utility of renal biopsy in these patients.¹⁸

The mainstay of management in GUTB is short-course chemotherapy regimen comprising four first-line antitubercular drugs for new patients.^{19 20} The standard 6-month regimen is adequate for the treatment of GUTB. The patient in the present case is in the continuation phase and responding well to the antitubercular therapy.

Learning points.

• Genitourinary tuberculosis poses a diagnostic challenge due to non-specific clinical manifestations.

• Conventional methods of diagnosis such as urine acid-fast bacilli smear and culture have low sensitivity.

• Role of positron emission tomography scan in renal tuberculosis needs further evaluation.

• The value of Xpert MTB/RIF in diagnosing renal tuberculosis needs further studies.