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Year : 2022  |  Volume : 10  |  Issue : 3  |  Page : 205-209

A case of fever of unknown origin – Was it really unknown?

Senior Consultant in Internal Medicine and Diabetes, Prem Health Care, Mysore, Karnataka, India

Date of Submission01-Nov-2020
Date of Acceptance14-Nov-2020
Date of Web Publication12-Jan-2022

Correspondence Address:
Dr. Manjunath Premanath
Nisarga, H. No. 21, Block 9, Madhuvana Layout, Srirampura II Stage, Mysore - 570 034, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_87_20

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A 66-year-old male patient with diabetes and hypertension presented with a history of 2 months of continuous fever and weight loss. He was investigated earlier and treated for upper respiratory infection, typhus, and other infections with no reduction in his fever. He had high eosinophilia and was investigated for malignancy and rheumatological diseases. Positron emission tomography-computed tomography scan revealed an increased uptake in the thyroid, and the thyroid profile clinched the diagnosis.

Keywords: Fever of unknown origin, malignancy, thyrotoxicosis, typhus

How to cite this article:
Premanath M. A case of fever of unknown origin – Was it really unknown?. APIK J Int Med 2022;10:205-9

How to cite this URL:
Premanath M. A case of fever of unknown origin – Was it really unknown?. APIK J Int Med [serial online] 2022 [cited 2022 Dec 2];10:205-9. Available from: https://www.ajim.in/text.asp?2022/10/3/205/335652

  Introduction Top

Fever of unknown origin (FUO) was defined long back as a temperature of >38.3°C on several occasions for >3 weeks and failure to arrive at a diagnosis despite a week of inpatient investigations.[1] This definition has been modified by the removal of in-hospital evaluation and exclusion of immunocompromised patients.[2] Chronic infection such as tuberculosis (TB) should be the first one to be thought off in India. Typhus infections which are prevalent in India should also be included in the differential diagnosis of FUO.[3] Drugs, infections, and malignancies form the other important causes of FUO. Hyperthyroidism is the most overlooked disorder where the clinical signs are either missed or absent, as a cause of FUO.[4] This is a case report of a patient who had persistent low-grade fever for >2 months with high-grade eosinophilia, which defied the diagnosis for a long time but ultimately proved to be from a common disease.

  Case Report Top

A 66-year-old male patient presented to the outpatient department on February 17, 2020, with the complaints of low-grade fever of >2 months. He had rigors to begin with, and had no history of cough. He was a known diabetic and hypertensive of >15 years on oral hypoglycemics and antihypertensives. He also complained of persistent low-grade headache. There was no history of rashes anywhere, nor arthralgia. The patient had pulmonary TB in 1970, which was treated well.

Past history revealed that he went to a doctor with a history of low-grade fever with dyspepsia of >2 weeks' duration on January 13, 2020, and was treated with proton pump inhibitors and paracetamol with no avail. He was seen by the same doctor 3 days later and was investigated for leptospira, malaria, and typhus. His Weil–Felix (W–F) reaction was OX-2-1:80. He was treated with doxycycline 100 mg BD with paracetamol. He was seen by an ENT surgeon on January 28, 2020, for throat pain, was diagnosed as chronic tonsillitis and pharyngitis, and was treated with levofloxacin 200 mg OD for 5 days and antihistamines. He continued to have fever throughout.

He was seen by an urologist on February 4, 2020, as the fever persisted, who put him on doxycycline again as his W–F reaction was OX-K 1:320 (>1:40), OX-2 1:160 (>1:40), and OX-19 1:160 (>1:40); erythrocyte sedimentation rate (ESR) was 70 mm/h, widal was negative, hemoglobin% was 13.4 g/dL (13.5–18), white blood cell-total count (WBC–TC) was 10,800 cells/mm3, neutrophils (N) was 43%, eosinophils (E) was 26% (1%–6%), lymphocytes (L) was 27%, macrophages (M) was 4%, and platelets was 298,000 cells/mm3. Blood picture showed mild toxic granules in neutrophils, severe eosinophilia, manteaux positivity (14 mm [<5 mm]), urine–albumin traces, and micro-3–4 pc/field.

As the fever continued, he was admitted in a hospital for a week for evaluation. His Adenosine Deaminase (ADA) was 20.2 (N <30), C-reactive protein was 1.72 (0–1), ESR was 90 mm/h (0–15), absolute eosinophil count (AEC) was 2200 cells/mm3 (40–440) and blood urea was normal, serum creatinine was normal, serum electrolytes were normal, and chest X-ray was normal [Figure 1]. Magnetic resonance imaging (MRI) of the brain [Figure 2] was done as he was complaining of headache, which showed a few lacunar infarcts. His MRI of the cervico-thoraco-lumbar spine showed mild cervical and lumbar spondylosis [Figure 3] and [Figure 4]. Ultrasound abdomen was normal [Figure 5]. The patient was put on doxycycline again along with his antidiabetic and antihypertensive drugs and was asked to continue for one more week. The fever did not subside.
Figure 1: Chest X-ray

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Figure 2: Magnetic resonance imaging brain

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Figure 3: Magnetic resonance imaging cervical spine

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Figure 4: Magnetic resonance imaging lumbosacral spine

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Figure 5: Ultrasound abdomen

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On examination on February 17, 2020, the patient was febrile; he had lost 6 kg of weight, blood pressure was 130/80 mmHg, and systemic examination was normal. As his eosinophilia persisted along with fever, malignancy was thought off, and he was sent for bone marrow biopsy. When bone marrow was normal, positron emission tomography-computed tomography (PET-CT) for any hidden malignancy was done along with antinuclear antibody (ANA) profile to rule out atypical presentation of rheumatological diseases.

The bone marrow biopsy was normal [Figure 6]a and [Figure 6]b; the section studied showed adequate bony trabeculae with intervening normocellular marrow. Megakaryocytes appeared within normal limits of morphology and distribution. Myeloid series showed hyperplasia with increase in the number of eosinophils and eosinophil precursors. The erythroid series were well represented. The section studied was negative for granulomas. The section for reticulin did not show any increase in reticulin fibers. PET-CT showed increased uptake of fluorodeoxyglucose in both lobes and the isthmus of the thyroid gland with multiple, varying sized nodules within the gland. Hence, the opinion was metabolically active thyroid gland – likely inflammatory [Figure 7]. Thyroid profile was done which showed thyroid-stimulating hormone (TSH) of <0.005 miU/mL. The ANA profiling was negative [Figure 8].
Figure 6: (a and b) Cytology of bone marrow biopsy

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Figure 7: Positron emission tomography-computed tomography

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Figure 8: Antinuclear antibody screen plus

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He was seen on March 2, 2020. His weight was 72.1 kg, still febrile. He was put on neo-mercazole 20 mg/day along with anti-inflammatory analgesics, and a small dose of steroids. He was seen a week later, and was feeling better; his weight was 72.9 kg and was afebrile. His ESR was 20 mm/h, and systemic examination was normal. He was asked to continue neo-mercazole along with propranolol 40 mg/day. Because of the CORONA outbreak, he came for follow-up on June 26, 2020. His weight was 78.8 kg, and he was afebrile; systemic examination was normal. Other findings were as follows: repeat T3 – 0.72 ng/mL (0.6–1.8), T4 – 5.8 μg/mL (4.5–12.6), TSH – 4.6 μIU/mL (0.35–5.5), WBC-TC – 9200 cells/mm3, Neutrophil (N) – 50, Lymphocytes (L) – 30, Eosinophils (E) – 15, M – 5, Basophils (B) – 0, and Absolute Eosinophil Count (AEC) – 1200 cells/mm3. The dosage of neo-mercazole was reduced to 15 mg daily. TSH on September 14, 2020, was 13.07 miU/mL. As the patient was going into hypothyroidism, neo-mercazole was stopped.

  Discussion Top

The patient in the present case already had fever for 2 months when he presented to our clinic. FUO is considered only when a patient continues to have fever with no response to treatment. The treatment of the present case was earlier based on the W–F test which was strongly positive for typhus, despite the absence of other symptoms and signs, and was repeatedly given doxycycline and other antibiotics. Rashes, myalgia, and eschar are seen in 55%–60% of cases of typhus.[5] Could the positive Weil-Felix test in this patient be false positive? False positive tests are commonly seen in typhoid, dengue and proteus infections. Depending only on serological positivity without any other features of the disease is not recommended.[3] In India, TB cannot be neglected in the diagnosis as this patient had a past history of TB, his ESR was high, there was loss of weight, and he had diabetes. His chest X-ray was normal and had no respiratory signs. Since Tuberculosis is common in India and patient showed features suggestive of it, starting anti tuberculous drugs is a common practice but it was not done in this case.[6] On presentation, eosinophilia was marked with an AEC of >2000 cells/mm3. Diseases with a very high eosinophil counts were thought of but were ruled out as this patient had only fever with no other signs of any of those conditions. Even then lymphoid malignancies where the eosinophils and their precursors are malignantly transformed resulting in Hodgkin's lymphoma and acute lymphoblastic leukemia had to be ruled out.[7] Because no obvious cause was found for his eosinophilia, trephine biopsy and cytogenetic analysis of the bone marrow were a must,[8] Hence a bone marrow biopsy with cytological analysis was done and the results came as normal. PET CT was done to show any hidden malignancies and his PET-CT done to show any other hidden malignancy surprisingly showed increased uptake in the thyroid, and with the TSH, the diagnosis was in the face and it was a simple one of subacute thyroiditis. A case report had shown similar results with an FUO.[9] It is said that 90% of patients with subacute thyroiditis would have thyroid pain and tenderness, but in some patients, typical features could be absent with only prolonged pyrexia and weight loss. Thyrotoxicosis is a common diagnosis that is often missed in the differential diagnosis of FUO.[4]

Hyper thyroidism as a cause of fever and weight loss, should have been thought of in this case much earlier that too when the patient did not respond to doxycycline. Fever is one of the symptoms of inflammation of thyroid gland, but it being the only manifestation is extreemly rare.[4] Perhaps weight loss in this case was ignored. The saying that FUO is more often an atypical presentation of a common disease rather than a common manifestation of a rare disease[2] was proved in this case. A thyroid profile could have avoided a lot of high profile investigations an misery to this patient. It should be done in all cases of prolonged fever before venturing into any higher investigations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Petersdorf RG, Beeson PB. Fever of unexplained origin: Report on 100 cases. Medicine (Baltimore) 1961;40:1-30.  Back to cited text no. 1
Bleeker-Rovers CP, Vander Meer JW. In: Jasper DC, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Fever of Unknown Origin in Harrison's Principles of Internal Medicine. 19th ed., Vol. 1, Ch. 26. USA: McGraw Hill; 2015. p. 135-41.  Back to cited text no. 2
Udayan U, Dias M, Machado S. A hospital based study of Rickettsial diseases evidenced by Weil–Felix test in a tertiary care hospital. CHRISMED J Health Res 2014;1:150-3.  Back to cited text no. 3
  [Full text]  
Pala NA, Ashraf M, Bhoughal BN. Profile of thyrotoxic patients presenting as pyrexia of unknown origin: An observational study from a tertiary care hospital. Int J Med Res Rev 2019;7:30-5.  Back to cited text no. 4
Peter JV, Sudarsan TI, Prakash JA, Varghese GM. Severe scrub typhus infection: Clinical features, diagnostic challenges and management. World J Crit Care Med 2015;4:244-50.  Back to cited text no. 5
Haftu H, Tadese K, Gebrehiwot T, Gebregziabher H. How common is eosinophilia in tuberculosis? Case report. Pediatric Health Med Ther 2020;11:59-63.  Back to cited text no. 6
Nutman TB. Evaluation of differential diagnosis of marked persistent eosinophilia. Immunol Allergy Clin North Am 2007;27:529-49.  Back to cited text no. 7
Butt NM, Lambert J, Ali S, Beer PA, Cross NC, Duncombe A, et al. Guidelines for the investigation and management of eosinophilia. Br J Haematol 2017;176:553-72.  Back to cited text no. 8
Bahowairath FA, Woodhouse N, Hussain S, Busaidi MA. Lessen of the month1: Subacute thyroiditis: A rare cause of fever of unknown origin. Clin Med (Lond) 2017;17:86-7.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3], [Figure 5], [Figure 6], [Figure 4], [Figure 7], [Figure 8]


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