Pyrexia Of Unknown Origin Biology Essay


A 65 year old gentleman presented with fever of six weeks with no localising symptoms except nonspecific urinary complaints. Clinica examination was unremarkable and his general condition was well preserved despite fever being recorded in-hospital. He gave a past history of treatment for abdominal tuberculosis and right sided nephrectomy for renal cell carcinoma more than a decade ago. He had recently undergone evaluation for renovasuclar hypertension in a solitary kidney with CT angiography followed by stenting of left renal artery. Extensive evaluation for infectious causes and recurrence of malignancy were negative. The fever showed no response to empirical therapy for urinary tract infection and enteric fever. Approach to a case of PUO is discussed. Patient was finally diagnosed to have a rare cause of fever possibly related to the stenting procedure.

Case summary

A 65 year old veteran presented with fever of six weeks duration. Fever was moderate grade, continuous, associated with chills, no rigors, associated with global headache and bodyache. He gave history of urgency & increased frequency of urination for 4 months. Patient admitted to fluid intake of 3-4 lit/day on advise of a private practitioner. No h/o precipitancy, dysuria, high colored urine or blood in urine, weight loss. No history of any other localising symptom. He has been investigated on OPD basis by a civil practitioner who based on raised Widal titres diagnosed as enteric fever. He had received empirical therapy with third generation cephalosporins and artesunate with no response.

Differentiate between fever, hyperpyrexia and hyperthermia.

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Fever is temperature elevation due to resetting of hypothalamic set point. When the temperature recorded is > 41.6oC (106oF), usually due to IC H'age, then it is labelled as hyperpyrexia. Hyperthyermia is characterized by an uncontrolled increase in body temperature that exceeds the body's ability to lose heat. The setting of the hypothalamic thermoregulatory center is unchanged in hyperthermia.

Define PUO. Does this patient qualify to have PUO ?

PUO was defined by Petersdorf and Beeson in 1961 as temperatures of >38.3°C (>101°F) on several occasions in a duration of fever of >3 weeks and failure to reach a diagnosis despite 1 week of inpatient investigation. Durack and Street prposed proposed a new system for

* MD, DNB, DM (Nephrology), Reader, Dept of Medicine, AFMC, Pune.

E mail: Tele: 020-26306012(O), 9545081656(M)

**MD, DNB, DM(Endocrinology), Cl spl (Med and Endocrinology), CH(SC) Pune.

E mail: Tele: 9823918983

classification of PUO: (1) classic PUO; (2) nosocomial PUO; (3) neutropenic PUO; and (4) PUO associated with HIV infection.

Classic PUO corresponds closely to the earlier definition of PUO, except that instead of mandatory requirement of one week's study in the hospital, three outpatient visits or inability to reach cause of fever within three days in the hospital or 1 week of "intelligent and invasive" ambulatory investigation. Nosocomial PUO is defined as when temperature of 38.3°C (101°F) develops on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission. Three days of investigation, including at least 2 days' incubation of cultures, is the minimum requirement for this diagnosis. Neutropenic FUO is defined as a temperature of 38.3°C (101°F) on several occasions in a patient whose neutrophil count is <500/L or is expected to fall to that level in 1-2 days. The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigation, including at least 2 days' incubation of cultures. HIV-associated FUO is defined by a temperature of 38.3°C (101°F) on several occasions over a period of >4 weeks for outpatients or >3 days for hospitalized patients with HIV infection.

Our patient qualifies to have classic PUO by the newer classification by Durrack and Street.

There is a past history of abdominal tuberculosis 18 yrs back, diagnosis being based on abdominal lymphnodes on ultrasound that responded well to antitubercular treatment. He is a hypertensive for last 18years on calcium channel blockers, β blockers and α receptor blockers. He was diagnosed to have renal cell carcinoma right kidney when he presented with flank pain 09 years back. He underwent nephrectomy right kidney with no recurrence thereafter. During investigation for poor blood pressure control he was found to have renal artery stenosis of the solitary left kidney on CT angiography three months ago. Lt renal artery was stented and the blood pressure control improved.

What are the differential diagnosis would you consider with the given history.

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In a 68 year old male presenting with fever of 6 wks, increased frequency of micturition, past history of abdominal TB, renal cell carcinoma and renal artery stenting, I would consider the following differential diagnosis.

UTI - Elderly males may have relapsing UTI especially due to persistent focus in the prostate

Tuberculosis - Any chronic illness with fever especially with a past history of TB keeps tuberculosis as a possibility. Genitourinary TB should be kept in mind considering the urinary symptoms.

Malignancy - In the elderly age group, malignancy like lymphoma presenting as fever is a strong possibility.

Recurrence of RCC - It is unusual for RCC to recur after 9 years, however the possibility cannot be ruled out.

Endocarditis - The patient underwent a renal artery stenting three months ago and has been febrile for 6 weeks. A subacute endocarditis also needs to be ruled out.

Statistically, what are the usual causes in broad categories of PUO? How does the Indian data differ from western data?

Infections, malignancies and connective tissue diseases account for the majority of cases. The spectrum of causes of PUO has been changing over the years. Due to refinement in the diagnostic procedures and imaging techniques, infections and malignancies get diagnosed more easily. In the data from the west, hence, undiagnosed cases have been accounting for larger number of cases. The relative importance of various causes of PUO varies between different series due to geographic variation in incidence of diseases. In Indian series of cases of PUO, infection especially tuberculosis is commoner than other causes. The data from two studies from Netherlands and one study from India is represented.

Harrison's TB of Internal Medicine- Modified from

de Kleijn et al. 19971

Study from Netherlands


Indian data3

Infections - 26%

Malignancy - 12.5%

Noninfectious Inflammatory Diseases - 24%

Miscellaneous Causes - 8%

Undiagnosed Causes -30%

Infection - 16 %

Malignancy - 7 %

Connective tissue diseases - 22 %

Miscellaneous - 4 %

No diagnosis - 51 %

Infections, especially tuberculosis (53%)

Neoplasms (17%)

Collagen vascular disorders (11%)

Miscellaneous causes (5%)

Undiagnosed (14%)

What are the causes of PUO of greater than 6 months duration?

When PUO lasts longer than 6 months then infectious and malignant causes decrease because they would be diagnosed, especially with the availability of current day sophisticated imaging methods. Factitious and unidentified causes become commoner in this group. Some patients will have no cause found despite extensive workup. These patients generally have a good prognosis.

Causes of PUO greater than 6 months4

Factitious causes 9 %

None identified 19 %

Miscellaneous causes 13%

No fever  27%

Infection 6 %

Neoplasm 7 %

Still's disease 6 %

Collagen vascular disease 4 %

Granulomatous hepatitis 8 %

Familial Mediterranean fever 3 %

Examination revealed an averagely built and nourished elderly male in good general condition with Wt - 65 kg, Ht - 160 cm, BMI - 25.39 kg/m2, T- 102ËšF, pulse 102/min, reg, Rt Radial weaker than Lt, BP 116/80 mmHg, RR - 16/min. No pallor, icterus, cyanosis, clubbing, pedal edema, significant lymphadenopathy or rash was noted. Abdomen examination revealed palpable liver 2cm below costal margin, soft, non tender, round margin, span - 14 cm. No splenomegaly or free fluid was present. Per rectal examination revealed enlarged prostate, firm, non tender, enlarged median lobe. Examination of other systems revealed no positive findings.

Investigations revealed Hb 12.3 g/dl, TLC7900/cumm, DLC P76L19, platelets 3.2 lac/cumm, peripheral smear was normocytic normochromic picture, Urine routine examination NAD, blood urea 42mg/dL, serum creatinine 1.5 mg/dL, serum Na 144 mmol/L, serum K 4.8 mmol/L, blood sugar fasting 107mg/dL and postprandial110 mg/dL, serum bilirubin 0.6mg/dL, AST 65IU/L, ALT 45 IU/L, calcium 9.8 mg/dL, phosphate 3.2mg/dL, Chest X Ray -NAD, ECG -NAD, USG Abd & pelvis - Liver - 13 cm, PV - normal, Spleen - 10.9 cm, RK - not visualised, LK - 11.5cm, No retroperitoneal lymphnodes, Urinary bladder showed minimal thickening of wall - 5mm with fine internal trabeculations, Prostate - 50gms, enlarged - 55Ã- 41Ã- 42,Gr II prostatomegaly with features of cystitis. Urine culture - Staph aureus ( coagulase negative) Repeat urine culture - E coli sensitive to imipenem and Meropenem, blood culture sterile, Uroflowmetry studies - normal, Urine for AFB x3- negative, Mantoux - negative, Quantiferon gold assay - negative, Widal - Neg, CRP - 22 mg/l - positive (normal <10 mg/l), cANCA, pANCA - Neg, Rheumatoid factor - Neg, ANA - Neg, HBsAg Negative, Anti HCV Negative, HIV - Non Reactor, Bone marrow c/s - No growth, Bone marrow studies - Reactive marrow, Weil Felix test -negative, Brucella c/s negative, Brucella Std Aggl test - negative.

With the available clinical findings and investigation results, what are your differential diagnosis and what would you do next?

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The only positive findings so far are pointing to a urinary tract infection with urine culture positivity for E coli and ultrasound evidence of cystitis. The prostatomegaly could be a site causing the relapsing infection. A course of imipenem as per the culture sensitivity may be tried. Tuberculosis and other infective causes seem unlikely. If there is no response, an underlying malignancy presenting as PUO is a possibility, especially in the elderly. Infective endocarditis should be considered in view of the recent angioplasty and stenting done to the renal artery. The mild azotemia is possibly due to CKD related to the hyperfiltration injury due to the solitary kidney and renovascular hypertension for which he had already been treated.

Name the malignancies that are known to present as PUO.

The malignancies known to present as PUO are Lymphoma, especially non-Hodgkin's, leukemia, renal cell carcinoma, hepatocellular carcinoma or other tumors metastatic to the liver, myelodysplastic syndrome, atrial myxoma and rarely multiple myeloma.

2D echo revealed no evidence of infective endocarditis. Patient was put on Imipenem and frequency of micturition decreased after fluid intake was restricted 1.5 - 2 lit/d but he continued to have fever with early morning rise in temperature and sweating. Weight loss of 3 Kg was documented in hospital from 65 to 61.5 Kg. Tumor markers CEA - 6.43 ng/ml (<2.5 ng/ml in a non-smoker and <5 ng/ml in smoker), PSA - 2.4 ng/ml ( <4 ng/ml). A PET-CT scan showed no e/o FDG (Fluorodeoxy Glucose) avid lesions to suggest active focus of infection. Metabolically active right cervical LN measuring 5mm with SUV of 3.2 was documented but was clinically not palpable or amenable to biopsy.The thyroid profile sent as routine showed T3 2.16 ng/l (N 0.8 - 2.2 ng/l), T4 21.16 mcg/l (N 5.5-13.5 mcg/L) and TSH < 0.01mIU/L (N 0.5-6.5 mIU/L). Tc 99m Thyroid Scan revealed decreased uptake in both lobes with uptake rate - 0.4%. In view of the poor uptake, the impression of the nuclear medicine specialist was that the scan was consistent with either a hypothyroid status or thyroiditis. In view of the biochemical evidence of thyrotoxicosis he was diagnosed as painless thyroiditis in thyrotoxic phase.

Classify thyroiditis.

Thyroiditis is traditionally classified as acute, subacute and chronic.


  Bacterial infection:

  Fungal infection

  Radiation thyroiditis after 131I treatment

  Amiodarone (may also be subacute or chronic)


  Viral (or granulomatous) thyroiditis

  Silent thyroiditis (including postpartum thyroiditis)

  Mycobacterial infection


  Autoimmunity: focal thyroiditis, Hashimoto's thyroiditis, atrophic thyroiditis

  Riedel's thyroiditis

  Parasitic thyroiditis: echinococcosis, strongyloidiasis, cysticercosis


A more clinically more useful classification would be

Thyroiditis with thyroid pain and tenderness 

Subacute (viral) thyroiditis

Infectious thyroiditis

Traumatic thyroiditis

Radiation thyroiditis

Thyroiditis without thyroid pain and tenderness

Painless thyroiditis

Postpartum thyroiditis

Fibrous thyroiditis

Drug-induced thyroiditis

What is the cause of painless thyroiditis?

Painless thyroiditis is considered to be a variant form of chronic autoimmune thyroiditis (Hashimoto's thyroiditis). Some patients with painless thyroiditis have high serum concentrations of antithyroid microsomal (thyroid peroxidase) and anti-thyroglobulin ab. It is known to be associated with specific HLA haplotypes, HLA-DR3. The factors postulated to initiate thyroiditis are excess iodine intake, amiodarone, interferon-alpha, interleukin-2, lithium, tyrosine kinase inhibitors, etanercept. The cytokines released in response to subclinical injury or infection might initiate the disorder.

What is the natural history of thyroiditis?

The natural history of thyroiditis follows three distinct phases over about 6 months:

thyrotoxic phase

hypothyroid phase

recovery phase

Each phase lasts about 4-6 wks. In the thyrotoxic phase, T4 and T3 levels are increased and TSH is suppressed. Thyroiditis is generally a self limiting illness.

The patient was diagnosed as a case of painless thyroiditis. The temperature started showing decreasing trend over the next 10 days. He was reassured and discharged. The patient became afebrile over the next 01 week and remained so thereafter. The thyroid profile done on followup after 2 months had normalised with a TSH level of 0.58 mIU/ml .

Final Diagnosis - Painless thyroiditis


Pyrexia of unknown origin (PUO) is a common clinical problem that challenges the clinician. The spectrum of causes of PUO has been changing over the years with undiagnosed cases increasing, usually consisting of benign and self limiting causes. Thyroiditis although uncommon, has been reported to be a cause of PUO. In patients with painful thyroiditis, there may be clinical clues to the diagnosis. Our patient had a painless thyroiditis making the diagnosis challenging. Painless thyroiditis usually takes a benign course and spontaneous recovery is the rule.

Take home message

1. The approach to the workup of PUO should be logical and systematic to avoid unnecessary expensive investigations.

2. Thyroiditis should be considered in the differential diagnosis of PUO after the more common diagnosis have been ruled out.

3. Thyroid function tests should figure in the battery of tests in evaluating patients of PUO