Pyrexia of unknown origin and its aetiology in Pakistan

Introduction

Pyrexia of unknown origin (PUO) is frequently defined as prolonged fever without any apparent initial cause. In 1961, Petersdorf and Beeson defined it as all of (i) illness of at least three weeks; (ii) fever of >38.3°C; (iii) and failure to reach a conclusive diagnosis after one week of hospitalization. ¹ This definition was extended in 1991 with “three outpatient visits or three days in the hospital”. ² PUO is divided into geographic region-specific classifications, which demands pertinent investigations according to the duration of symptoms. Furthermore, PUO is broadly classified into classic, nosocomial, neutropenic, and human immunodeficiency virus (HIV)-related fever.

Diagnosing patients labelled as PUO is frequently a challenge in clinical practice. It is because there is an extensive list of differential diagnoses, spreading across all medical specialties. It requires extensive experience, and thorough knowledge to reach the correct diagnosis. Despite advancement in contemporary diagnostic modalities, 20% of patients still remain undiagnosed. ²

Methods

Our hospital-based observational study was performed retrospectively with patient chart reviews and electronic data retrieval between January 2018 to December 2021 in Abbas Institute of Medical Sciences (ID # 10/12/21/AIMS). All patients >5 years of age who met the 1991 criteria were enrolled. ² Chemotherapy-induced and HIV Immuno-compromised patients, and those who developed a fever after hospital admission, were excluded. A standard protocol was followed for diagnosis. ³

Statistical Package for the Social Sciences (SPSS) version 26 (IBM Corp., Armonk, NY, USA.) was used for data synthesis. Continuous variables were presented as mean ± standard deviation (SD) or median and interquartile range (IQR) while categorical data were expressed as frequency (n) and percentages (%). Fischer's exact test was used to analyze categorical data in various etiologies of PUO. A p < 0.05 was considered significant.

Results

A total of 412 patients were enrolled in our study. Clinical characteristics of PUO are presented in Table 1. Causes of PUO are tabulated in Figure 1 (Supplementary Table 1). Diagnostic investigations used to diagnose PUO in our cohort are shown in Figure 2 (Supplementary Table 2).

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Figure 1.

Aetiology of PUO. Made on biorender.com by J.M.

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Figure 2.

Diagnostic investigations for PUO.

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Table 1.

Clinical characteristics.

Variables	n (%)
Age (years)	Median: 37.25 (5 – 84)
Age range
5 – 20	114 (27.6)
20 – 40	157 (38.1)
40 – 60	83 (20.1)
60 – 80	51 (12.2)
> 80	7 (1.6)
Females	165 (40)
Duration of fever (weeks)	Median: 26 (3–54)
Type of fever
Low-grade (< 40 °C)	300 (72.8)
High-grade (≥ 40 °C)	112 (27.1)
Symptoms
Weight loss	241 (58.4)
Cough	158 (38.3)
Abdominal pain	142 (34.4)
Arthralgia	134 (32.5)
Nausea	93 (22.5)
Dyspnea	66 (16)
Backache	11 (2.6)
Diarrhea	5 (1.2)
Disorientation	5 (1.2)
Constipation	4 (0.9)
Xerostomia	3 (0.7)
Signs
Lymphadenopathy	164 (39.8)
Arthritis	127 (30.8)
Splenomegaly	91 (22)
Hepatomegaly	85 (20.6)
Cardiac murmurs	18 (4.3)
Rash	15 (3.6)
Ascites	7 (1.6)
Anasarca	3 (0.7)

Discussion

In our study, a definitive diagnosis in the majority of subjects was reached following the diagnostic criteria of Durack and Street. ² A step-wise approach to the diagnosis of PUO is more useful as compared to empirical treatment protocol with extensive treatment regimens and investigations. This approach is demonstrated in Figure 3, and actually consists of two stages, one clinical and the other investigative. If a clinical diagnosis is apparent (which is rarely the case), treatment is started after conducting focused investigations towards confirmation of the cause. If, however, no clinical clue is available, the investigative approach is conducted, which includes basic laboratory and imaging tests, specialized blood cultures, viral serology, and advanced CT imaging. Invasive investigations are later used if imaging produces no definite clues.

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Figure 3.

Step-wise diagnostic algorithm. Made on biorender.com by J.M.

We found tuberculosis to be the predominant infection in all age groups. ⁴ It can be disseminated, or present in virtually any organ, including atypical pulmonary manifestations. ⁵ Therefore, it is always the foremost diagnosis in the minds of our clinicians.

In endemic areas, enteric fever, brucellosis, and infective endocarditis are important causes of PUO, as in our experience, but haematological malignancies were as common. ⁶ They can cause non-specific symptoms and prolonged fever and may engender a significant delay in diagnosis. This usually occurs owing to an erroneous interpretation of lymph node histology as reactive lymphoid hyperplasia.

For inflammatory conditions, such as rheumatoid arthritis and systemic lupus erythematosus, a wide array of diagnostic tests are available. They therefore do not present as PUO as they did a decade ago. Nonetheless, vasculitides, sarcoidosis, and Histiocytosis X are frequently missed diagnoses, largely owing to the myriad of symptoms and clinical manifestations with which they present. ⁷

Fungal infections, however, remain rare and are usually limited to immunocompromised patients.^8,9 Geographical variation is key, and thus a regular update of studies like ours is important.

Conclusion

A step-wise approach to diagnose PUO is useful in a low-resource setting; it is possible to diagnose the majority of cases using clinical knowledge and targeted investigations. Atypical manifestations of common diseases are more likely than rare conditions. However, rare conditions can often present as PUO. Given the epidemiological diversity of such diseases, a localized algorithm for every region will help in minimizing delays to diagnosis and aid initiation of prompt treatment.

Supplemental Material

Supplemental Material