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Fever of Unknown Origin (PUO): Unravelling the Mystery Behind a Fever

Did you know that approximately 10-15% of all fevers worldwide fall under the enigmatic category of Fever of Unknown Origin (FUO)? Fever has been a symptom of various ailments throughout human history. While many fevers resolve on their own or with straightforward medical intervention, a subset defies easy diagnosis—Fever of Unknown Origin (PUO). 


In this blog, we’ll talk about fever of unknown origin(Pyrexia), its historical context, types, common causes, diagnostic challenges, advanced diagnostic techniques, and treatment approaches.


Historical Perspective


The term "Fever of Unknown Origin" has evolved over time, mirroring the advancements in medical knowledge. Pyrexia is another name for PUO. Early medical texts often detailed fevers without immediate identification. The formal recognition of PUO occurred in the 20th century, influenced by documented cases from notable physicians, shaping our grasp of this mysterious condition.


Types of PUO


Fever of Unknown Origin (PUO), or Pyrexia, is not a singular entity but a spectrum of conditions that share the common characteristic of persistent fever without an immediately apparent cause. Understanding the various types of PUO is crucial for tailoring diagnostic approaches and formulating effective treatment strategies. Let's delve into the nuances of each type:

  • Classic PUO:
      1. Definition: A fever persisting for more than three weeks with an uncertain diagnosis despite thorough investigation.
      2. Clinical Challenges: Classic PUO poses diagnostic challenges due to the broad range of potential causes, requiring a systematic and comprehensive approach to unravel the mystery behind the fever.
      3. Examples of Causes: Infections, inflammatory disorders, neoplastic conditions, and less common factors like drug-induced fever.


  • Nosocomial PUO:
      1. Definition: Fever developing during a hospital stay and persisting for at least three days, excluding infections incubating on admission.
      2. Clinical Challenges: Identifying the cause of nosocomial fever can be complex due to the multitude of factors present in a hospital setting, including healthcare-associated infections, reactions to medications, or underlying comorbidities.
      3. Examples of Causes: Hospital-acquired infections, adverse drug reactions, device-related complications.


  • Neutropenic PUO:
      1. Definition: A fever arising in individuals with a low neutrophil count (neutropenia), often associated with conditions like chemotherapy or bone marrow disorders.
      2. Clinical Challenges: Neutropenic patients are particularly vulnerable to infections, and determining the source of fever requires careful consideration of potential pathogens and rapid intervention to prevent complications.
      3. Examples of Causes: Bacterial, fungal, or viral infections in immunocompromised individuals.


  • HIV-Associated PUO:
    1. Definition: Fever persisting for more than four weeks in individuals living with HIV, with an uncertain diagnosis.
    2. Clinical Challenges: HIV-associated PUO can be attributed to various factors, including opportunistic infections, neoplastic processes, or autoimmune disorders, necessitating a comprehensive evaluation.
    3. Examples of Causes: Tuberculosis, atypical infections, lymphomas, immune reconstitution inflammatory syndrome (IRIS).


Common Causes of PUO


Maintaining optimal vaginal health involves a delicate balance between cleanliness and allowing the body's natural mechanisms to function. Let's discuss the nuances of feminine hygiene, debunking myths, and providing practical tips for a healthy vaginal environment.

  • The Dos and Don'ts of Cleansing:
      1. Do: Embrace a gentle approach to cleansing. Warm water and mild, fragrance-free soap are often sufficient for maintaining cleanliness without disrupting the natural pH balance.
      2. Don't: Succumb to the allure of douching. Despite misconceptions, douching can upset the delicate ecosystem of the vagina, potentially leading to imbalances and infections.


  • Natural Cleansing Methods:
      1. Water: A simple yet effective method for maintaining cleanliness is using warm water during showers. The gentle flow helps rinse away impurities without causing irritation.
      2. Mild Soaps: When opting for soap, choose mild, pH-balanced options. Harsh soaps or those with strong fragrances can strip away natural oils and disrupt the acidic pH of the vagina.


  • Understanding Menstrual Hygiene:
      1. Product Choices: The products used during menstruation play a crucial role in vaginal health. Opt for sanitary pads or tampons made from breathable materials like cotton to minimise the risk of irritation.
      2. Regular Changes: Changing sanitary products regularly is essential. Prolonged use can create a breeding ground for bacteria and increase the likelihood of infections.


  • Choosing Breathable Innerwear:
      1. Material Matters: Select innerwear made from breathable fabrics, such as cotton. This helps prevent excessive moisture buildup, reducing the risk of fungal infections.
      2. Avoiding Tight Clothing: Tight-fitting clothing can restrict airflow, leading to increased warmth and moisture. Opt for looser clothing whenever possible to promote ventilation.


  • Balancing Act of Intimate Washes:
    1. pH-Balanced Products: PH-balanced products are to be used after discussion with the doctor.
    2. Minimal Additives: Read product labels carefully. Choose intimate washes with minimal additives and fragrances to minimise the risk of allergic reactions or irritation.


Diagnostic Challenges


The diagnosis of PUO is often fraught with challenges. The elusive nature of the condition demands a meticulous and comprehensive approach. Physicians rely on thorough medical histories, detailed physical examinations, and various laboratory tests. Despite these tools, reaching a definitive diagnosis can be a prolonged and frustrating process, causing physical and emotional distress for the patient.


Advanced Diagnostic Techniques


As technology advances, so do the tools available for diagnosing PUO. Imaging modalities, such as computed tomography (CT) scans and positron emission tomography (PET) scans, offer valuable insights into areas that may be harbouring the elusive cause. 


Molecular and genetic testing bring a level of precision previously unavailable, enabling clinicians to identify pathogens or genetic abnormalities that may underlie the fever. Invasive procedures like biopsies provide histopathological evidence crucial for a conclusive diagnosis.


Treatment Approaches


Managing PUO involves addressing the underlying cause, when identified, and alleviating symptoms while awaiting a definitive diagnosis. Antimicrobial therapy addresses infectious causes, while inflammatory conditions may require immunosuppressive agents, and neoplastic diseases may call for chemotherapy. Supporting the patient's well-being is vital during the diagnostic process.


Living with an undiagnosed fever carries a psychological toll. Uncertainty about health can induce stress, anxiety, and depression. Healthcare providers must not only attend to the physical aspects of PUO but also offer emotional support and resources to help patients navigate the challenges of the diagnostic journey.




In unravelling the mystery behind Fever of Unknown Origin, we navigate through a realm where uncertainty meets the resilience of medical science. PUO is not merely a medical challenge; it is a journey that requires patience, collaboration, and a commitment to advancing our understanding of the complexities that underlie seemingly inexplicable fevers.

Dr. Akanksha Rastogi
Internal Medicine
Meet The Doctor
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