Nosocomial FUO - Causes, Diagnosis, and Treatment

Introduction

Nosocomial fever of unknown origin (FUO) is described as a temperature of 101 degrees Fahrenheit or greater for a duration of at least three weeks with no established diagnosis, even after one week of investigative procedures. The condition also includes immunocompromised individuals, including those with human immunodeficiency virus (HIV). Nosocomial fever is a sign of healthcare-associated infection.

What Is Nosocomial Fever?

• Fever that occurs greater than 48 hours after hospital admission.

• The prevalence of nosocomial fever varies between 2 % to 36 %.

• Fever occurs due to the interaction between proinflammatory cytokines (signaling molecules secreted by inflammatory cells), the hypothalamus (a small part of the brain that controls vital body functions), and cellular and end-organ systems.

• This specific region is triggered by microorganisms, exogenous pyrogens (substances that induce fever), tissue inflammation (the body’s response to tissue damage), ischemia (reduced blood flow), or injury.

• Nosocomial fever can originate from non-infectious causes.

• 40 % to 70 % of patients have infectious etiology occurring from hospital-associated infections.

• The fever may arise from antimicrobial-resistant organisms. This results in prolonged hospital stay, high costs, and fatality.

What Are the Causes of Fever?

The causes can be classified into infectious, non-infectious, malignancy, and miscellaneous origin.

Non-infectious Inflammatory Causes

1. Giant Cell Arteritis- Swelling and redness occurring in the inner wall of arteries.

2. Adult Still Disease - A disease in which redness and swelling appear in the entire body.

3. Systemic Lupus Erythematosus- A chronic disease where the immune cells attack normal cells resulting in severe tiredness and joint pain.

4. Periarteritis Nodosa- It is a blood vessel disease that can cause injury to internal organs.

5. Rheumatoid Arthritis- A disorder where swelling and stiffness occur at joints.

Infectious Causes of Fever

1. Tuberculosis- A severe bacterial infection of the lungs.

2. Q Fever- A bacterial infection that occurs in humans and animals.

3. Brucellosis- A infectious bacterial disease caused by consuming undercooked meat or unpasteurized milk.

4. HIV (Human Immunodeficiency Virus) Infection- It is a disease that spreads sexual contact, drug abuse, or infected blood.

5. Organ-Based Infectious- It includes subacute bacterial endocarditis (bacterial infection of the heart) and chronic sinusitis.

6. Tickborne Infections- The disease includes babesiosis (parasite infecting red blood cells) and anaplasmosis (tickborne bacterial disease affecting red blood cells leading to fever and anemia).

Regional Infections: Histoplasmosis (fungal infection affecting lungs) and coccidioidomycosis (respiratory illness caused by inhaling fungus).

Malignant (Cancer) And Neoplastic Causes of FUO

1. Lymphoma- A cancer of the lymphatic system.

2. Renal Cell Carcinoma- A form of kidney cancer.

3. Myeloproliferative Disorder- Blood cancer caused by changes in stem cells of bone marrow.

4. Multiple Myeloma- A rare form of blood cancer affecting plasma cells.

Miscellaneous Causes of FUO

1. Cirrhosis- Liver damage.

2. Drug Fever- It develops due to a hypersensitivity reaction to specific drugs like diuretics, pain medications, antiarrhythmic drugs, antiseizure drugs, sedatives, specific antibiotics, antihistamines, barbiturates, cephalosporins, salicylates, and sulfonamides such as Allopurinol, Captopril, Cimetidine, Clofibrate, Erythromycin, etc.

3. Thyroiditis - A condition with swelling and redness of the thyroid gland.

4. Crohn's Disease- A disease where swelling and redness occurs in the lining of the digestive tract.

5. Pulmonary Emboli- Blood clot in arteries of lungs.

Nosocomial FUO Specific Causes

Healthcare-associated fever can be due to the following causes.

1. The Infectious Causes- Include nosocomial pneumonia (pneumonia occurring within 48 hours of hospital admission), Clostridium difficile infection (bacterial infection causing redness and swelling of the colon), pyelonephritis (kidney infection), device-related (urinary catheter and heart pacemakers) or viral diseases.

2. Drug Fever- Antibiotics, beta-lactams, and diphenylhydantoin are responsible for developing a fever.

3. Post-operative Complications- It can cause infections that result in fever occurrence.

4. Venous Thromboembolic Diseases- Diseases such as thrombosis (obstruction of blood vessels with clots), embolism (blockage of the artery), or septic thrombophlebitis (clots in veins that are infected with bacteria) are some examples.

5. Malignancy- Infected tumors result in fever.

6. Transfusion-Related Reactions- These cause the patients to develop fever and chills.

7. Central Nervous System Disorders- Some neurologic disorders cause fever.

8. Bowel Ischemia- A reduced blood flow causes pain and abnormal functioning of blood vessels

9. Perforation- A hole formation in the wall of an organ.

10. Hematoma- A swelling of clotted blood in tissues.

11. Gout- Pain and redness caused by urate crystal accumulation in joints.

12. Sinusitis- It occurs in patients with nasogastric or nasotracheal intubation. The condition can develop into a fever of unknown origin.

What Are the Symptoms of a Fever of Unknown Origin?

• Temperature exceeding 100.4 degrees Fahrenheit in babies and 99.5 degrees Fahrenheit in children or adults.

• Sweating.

• Chills.

• Headache.

• Body or joint aches.

• Weakness.

• Sore throat.

• Fatigue.

• Cough.

• Rash.

• Sinus congestion.

What Are the Diagnostic Criteria for Nosocomial FUO?

Diagnostic clues are not available with physical examination and require frequent examination.

History:

• Family history.

• Immunization history.

• Occupational history.

• Travel history.

• Nutrition and weight history.

• Drug history of consuming over-the-counter medications or illicit substances.

• Recreational habits.

• Animal contacts.

• History of surgery, trauma, or procedures.

Fever Patterns:

Analyzing fever patterns can provide clues to the cause of the fever’s origin.

• Pel-Ebstein fever in Hodgkin's disease appears as a week-long high fever with remission periods that are week long.

• Patients with cyclic neutropenia have periodic fevers.

• Double quotidian fever with two spikes a day appears in adults Still disease, malaria, and typhoid.

Physical Examination:

• Intraabdominal abscess, perinephric abscess, and psoas abscess have a previous history of abdominal surgery, trauma, peritonitis, endoscopy, and urologic or gynecological procedures.

• Review of unintentional weight loss.

• Age-appropriate cancer screening.

• Smoking or alcohol use.

• The presence of bradycardia is suggestive of lymphoma or central nervous system malignancy.

• New heart murmur pointing towards atrial myxoma.

• Sternal tenderness is indicative of the myeloproliferative disorder.

• Isolated hepatomegaly and fever of unknown origin are suggestive of hepatoma or liver metastasis.

• Hepatomegaly without splenomegaly suggests rheumatological disorders.

Diagnostic Evaluation:

Noninvasive Tests.

• Complete blood count with differential.

• Complete metabolic test.

• Liver function tests.

• Urine analysis with microscopy and urine culture.

• Three sets of blood cultures are evaluated from different sites several hours apart and before the initiation of antibiotic therapy.

• Erythrocyte sedimentation rate.

• Antinuclear antibody.

• Abdominal sonograph or pelvic sonography is used to rule out malignancy in the abdomen.

• Computed tomography (CT) scans. A disadvantage of radiographic imaging like CT is a false-positive result due to scars, fibrosis, or other benign conditions.

• Clostridium difficle toxins must be evaluated.

Nuclear Medicine Tests.

• Fluorodeoxyglucose positron emission tomography is used to analyze fever of unknown origin. They are highly sensitive and non-invasive procedures. The test is helpful for the anatomic localization of infectious, inflammatory, or neoplastic processes.

• Gallium and indium-labeled leukocyte studies enable diagnosis.

Invasive Tests.

Biopsies of lymph nodes, liver, bone marrow, epididymal nodule, and temporal artery are associated with invasive tests for fever of unknown origin. Enlarged lymph nodes must be diagnosed with a biopsy. The examination can detect malignancy, myeloproliferative disorders, and specific infections. Whereas, bone marrow biopsies are used in the detection of leukemias, lymphomas, and myelomas. Other invasive procedures like endoscopic examinations can detect gastrointestinal tumors.

How Are Nosocomial FUO Treated?

Due to variations in etiology, there is no specific treatment.

• Antibiotics or steroids are not indicated until the patient is neutropenic. There is a risk of masking the main features of the disease.

• Patients with a fever of unknown origin do not require surgery.

• Patients suspected of drug fever are advised to discontinue the drug. The patient will be afebrile two days after drug discontinuity.

• In patients with untreated nosocomial fever, there is a risk of developing nosocomial pneumonia.

• Patients who develop drug fever to specific medications are prescribed a different medication.

• Patients with a fever of unknown origin have good outcomes. Most patients have their symptoms resolved with no intervention. However, few patients may develop complications that may be fatal.

Conclusion

Most nosocomial fevers of unknown origin are difficult to diagnose and resolve without treatment. A wide variety of diseases are responsible for disease development. An investigative approach involving laboratory, imaging studies, and invasive procedures helps provide a better diagnosis of the underlying causes of the condition.