4.9 Fever of Unknown Origin, Neutropenic Fever & Toxic Shock

ABIM Internal Medicine Exam

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1 Chapter 0: The ABIM Exam, Blueprint & Study Strategy

0.1 Exam Format, Question Types & the 2026 Blueprint 0.2 Eligibility, Registration, Fees & Exam-Day Logistics 0.3 Scoring, the Passing Standard & Score Reports 0.4 Building a Blueprint-Weighted Study Plan

2 Chapter 1: Cardiovascular Disease (14% of Exam)

1.1 Ischemic Heart Disease & Acute Coronary Syndromes 1.2 Antithrombotic Therapy, Secondary Prevention & Mechanical Complications of MI 1.3 Atrial Fibrillation, Atrial Flutter & Stroke Prevention 1.4 Supraventricular Tachycardias, Ventricular Arrhythmias & Bradycardias 1.5 Heart Failure: Classification, Staging & Guideline-Directed Medical Therapy 1.6 Device Therapy, HFpEF & the Cardiomyopathies 1.7 Valvular Heart Disease & Endocarditis Prophylaxis 1.8 Pericardial Disease & Acute Aortic Syndromes 1.9 Hypertension: Classification, Diagnosis & Secondary Causes 1.10 Hypertensive Crises & Dyslipidemia 1.11 Adult Congenital Heart Disease & Coarctation of the Aorta 1.12 Syncope: Reflex, Orthostatic & Cardiac Causes 1.13 Cardiac Physical Examination, Murmurs & Antithrombotic Selection

3 Chapter 2: Endocrinology, Diabetes & Metabolism (9% of Exam)

2.1 Diabetes Mellitus: Diagnosis, Glycemic Targets & Pharmacotherapy 2.2 Insulin Therapy, Hyperglycemic Emergencies & Chronic Complications 2.3 Thyroid Function Testing & Hypothyroidism 2.4 Thyrotoxicosis, Thyroid Storm & Thyroid Nodules 2.5 Adrenal & Pituitary Disorders 2.6 Hypercalcemia, Hypocalcemia & Disorders of Mineral Metabolism 2.7 Osteoporosis & Paget Disease of Bone 2.8 Ovarian, Testicular & Reproductive Endocrine Disorders 2.9 Hypoglycemia, Endocrine Tumors, Polyglandular Syndromes & Severe Hypertriglyceridemia

4 Chapter 3: Gastroenterology & Hepatology (9% of Exam)

3.1 Esophageal Disease 3.2 Stomach & Duodenal Disease and Gastrointestinal Hemorrhage 3.3 Inflammatory Bowel Disease 3.4 Celiac Disease & Irritable Bowel Syndrome 3.5 Diverticular Disease & Colorectal Cancer Screening 3.6 Viral Hepatitis, Steatotic & Alcohol-Associated Liver Disease 3.7 Cirrhosis & the Complications of Portal Hypertension 3.8 Acute Pancreatitis 3.9 Chronic Pancreatitis & Biliary Tract Disease 3.10 Inherited, Autoimmune & Drug-Induced Liver Disease 3.11 Small Intestinal Disease, Ischemia & Gastrointestinal Complications of HIV

5 Chapter 4: Infectious Disease (9% of Exam)

4.1 Lower Respiratory Tract Infections & Sepsis Syndromes 4.2 Viral Respiratory Pathogens & Tuberculosis 4.3 Central Nervous System Infections 4.4 Skin, Soft Tissue, Bone & Joint Infections 4.5 Infective Endocarditis & Cardiovascular Infection 4.6 Clostridioides difficile & Catheter-Related Bloodstream Infection 4.7 HIV Diagnosis, Antiretroviral Therapy & Prevention 4.8 Opportunistic Infections & Sexually Transmitted Infections 4.9 Fever of Unknown Origin, Neutropenic Fever & Toxic Shock 4.10 Travel-Related Illness, Vector-Borne Disease & Outbreaks 4.11 Infection Prevention, Nosocomial Infection & Postexposure Prophylaxis 4.12 Rheumatic Fever, Poststreptococcal Disease, Enteric & Hepatic Infections

6 Chapter 5: Pulmonary Disease (9% of Exam)

5.1 COPD: Diagnosis, GOLD Classification & Initial Pharmacotherapy 5.2 Interventions That Reduce COPD Mortality & Exacerbation Management 5.3 Asthma: Diagnosis, Stepwise Therapy & Status Asthmaticus 5.4 Interstitial Lung Disease & Idiopathic Pulmonary Fibrosis 5.5 Sarcoidosis, Hypersensitivity Pneumonitis & Occupational Lung Disease 5.6 Pulmonary Embolism: Diagnosis, Risk Stratification & Anticoagulation 5.7 Pulmonary Hypertension & Sleep-Disordered Breathing 5.8 Acute Respiratory Distress Syndrome & Mechanical Ventilation 5.9 Pleural Disease, Empyema & Pneumothorax 5.10 Bronchiectasis, Cystic Fibrosis & Restrictive Lung Disease 5.11 Evaluation of Cough, Dyspnea, Hemoptysis & the Solitary Pulmonary Nodule

7 Chapter 6: Rheumatology & Orthopedics (9% of Exam)

6.1 Rheumatoid Arthritis: Diagnosis & Systemic Manifestations 6.2 Antirheumatic Pharmacotherapy & the Spondyloarthropathies 6.3 Gout: Pathophysiology & Acute Management 6.4 Urate-Lowering Therapy & Calcium Pyrophosphate Deposition Disease 6.5 Osteoarthritis 6.6 Systemic Lupus Erythematosus 6.7 Systemic Sclerosis, Sjogren Syndrome & Inflammatory Myopathies 6.8 The Vasculitides 6.9 Regional Musculoskeletal Syndromes, Back Pain & Sports Injuries 6.10 Other Primary Rheumatic Disorders & Mixed Connective Tissue Disease 6.11 Osteonecrosis & Metabolic Bone Disease

8 Chapter 7: Hematology (6% of Exam)

7.1 Approach to Anemia & the Microcytic Anemias 7.2 Macrocytic, Normocytic & Hemolytic Anemias 7.3 Hemoglobinopathies, Thalassemias & Paroxysmal Nocturnal Hemoglobinuria 7.4 Platelet Disorders, Thrombocytopenia & the Bleeding Patient 7.5 Coagulation Factor Disorders, Thrombophilia & Anticoagulant Reversal 7.6 Acute Leukemias, Chronic Leukemias & Myeloproliferative Neoplasms 7.7 Lymphomas & Plasma Cell Disorders 7.8 Myelodysplastic Syndrome, Myeloproliferative Neoplasms & Porphyria 7.9 Transfusion Medicine & Late Complications of Transplantation

9 Chapter 8: Medical Oncology (6% of Exam)

8.1 Breast, Lung, Colorectal & Prostate Cancer 8.2 Oncologic Emergencies 8.3 Genitourinary & Gynecologic Malignancies 8.4 Head and Neck, Bone & Soft Tissue Cancer and Cancer of Unknown Primary 8.5 Complications of Cancer & Its Treatment 8.6 Cancer Prevention, Survivorship & Psychosocial Care

10 Chapter 9: Nephrology & Urology (6% of Exam)

9.1 Acute Kidney Injury: Staging, Etiology & Urine Microscopy 9.2 Glomerular Disorders & Nephrotic Syndrome 9.3 Nephritic Syndromes, RPGN & Indications for Renal Replacement Therapy 9.4 Chronic Kidney Disease: Staging & Progression Retardation 9.5 Complications of Chronic Kidney Disease: Anemia, CKD-MBD & Acidosis 9.6 Hyponatremia, Hypernatremia & Water Balance 9.7 Potassium Disorders & Systematic Acid-Base Analysis 9.8 Renal Tubular Acidosis & Nephrolithiasis 9.9 Prostate Disorders, Urinary Incontinence & Other Urologic Conditions 9.10 Cystic Kidney Disease, Obstructive Uropathy, Tubulointerstitial Disease & Hematuria

11 Chapter 10: Neurology (4% of Exam)

10.1 Acute Ischemic Stroke: Syndromes & Reperfusion 10.2 Transient Ischemic Attack, Secondary Prevention & Hemorrhagic Stroke 10.3 Headache & Facial Pain 10.4 Seizures, Epilepsy & Movement Disorders 10.5 Multiple Sclerosis & Neuromuscular Junction Disorders 10.6 Motor Neuron Disease & Acute Peripheral Neuropathy 10.7 Cranial Neuropathies & Neuro-Ophthalmology 10.8 Peripheral Neuropathies, CNS Tumors & Other Neurologic Disorders

12 Chapter 11: Psychiatry & Behavioral Health (4% of Exam)

11.1 Major Depressive Disorder & Medical Mimics 11.2 Antidepressant Pharmacotherapy & Treatment-Resistant Depression 11.3 Bipolar Disorder, Mood Stabilizers & Lithium Toxicity 11.4 Anxiety, Stress-Related & Obsessive-Compulsive Disorders 11.5 Alcohol Use Disorder & Withdrawal 11.6 Pharmacotherapy for Alcohol & Opioid Use Disorder 11.7 Toxidromes, Psychiatric Emergencies & Suicide Risk Assessment 11.8 Psychotic, Somatic Symptom, Factitious & Personality Disorders 11.9 Eating Disorders, Sleep Disorders & Sexual Health

13 Chapter 12: Dermatology (3% of Exam)

12.1 Dermatitis, Papulosquamous & Inflammatory Dermatoses 12.2 Acne, Rosacea & Cutaneous Infections 12.3 Herpes Zoster & Autoimmune Blistering Diseases 12.4 Nodules, Tumors & Cutaneous Oncology 12.5 Dermatologic Emergencies & Severe Cutaneous Adverse Reactions 12.6 Pigment Disorders, Alopecia, Nail Disease & Photosensitivity 12.7 Vascular Dermatoses, Environmental Injury & Cutaneous Signs of Systemic Disease

14 Chapter 13: Obstetrics & Gynecology / Women's Health (3% of Exam)

13.1 Contraception, Preconception Care & Teratogenicity 13.2 Hypertensive Disorders of Pregnancy & Gestational Diabetes 13.3 Thyroid Disease & Venous Thromboembolism in Pregnancy 13.4 Menopause & Menopausal Hormone Therapy 13.5 Abnormal Uterine Bleeding, Endometrial Disease & Gynecologic Cancer Screening 13.6 Breast Disorders & Diseases of the Vulva and Vagina 13.7 Menstrual Disorders, Fibroids, Endometriosis & Early Pregnancy Complications

15 Chapter 14: Geriatric Syndromes (3% of Exam)

14.1 Comprehensive Geriatric Assessment & Frailty 14.2 Falls, Gait Assessment & Polypharmacy 14.3 Urinary Incontinence & Pressure Injuries in Older Adults 14.4 Mild Cognitive Impairment, Dementia & Its Subtypes 14.5 Delirium & the Pharmacotherapy of Cognitive Disorders 14.6 Palliative Care, Hospice & Advance Care Planning 14.7 Chronic Wounds, Nutrition, Swallowing, Constipation & Hip Fracture 14.8 Sensory Impairment, Dizziness, Elder Mistreatment & Care Settings

16 Chapter 15: Allergy & Immunology (2% of Exam)

15.1 Anaphylaxis: Recognition & Emergency Management 15.2 Urticaria & Angioedema 15.3 Drug Allergy, Desensitization & Adult Immunodeficiency 15.4 Food Allergy, Insect Venom Hypersensitivity, Serum Sickness & Contrast Reactions 15.5 Rhinitis, Conjunctivitis, Eosinophilic & Mast Cell Disorders

17 Chapter 16: Preventive Medicine, Immunization & Clinical Epidemiology

16.1 The USPSTF Framework & Evidence-Based Cancer Screening 16.2 Cardiovascular & Metabolic Screening and Primary Prevention 16.3 Adult Immunization & Vaccines in Special Populations 16.4 Clinical Epidemiology, Biostatistics & Study Design

18 Chapter 17: Miscellaneous - Ethics, Patient Safety & Quality Improvement (2% of Exam)

17.1 Principles of Bioethics & Decisional Capacity 17.2 Informed Consent, Treatment Refusal & Special Scenarios 17.3 Surrogate Decision-Making, Advance Directives & Confidentiality 17.4 Patient Safety Science, Medical Error & Diagnostic Reasoning 17.5 Quality Improvement Methods, Health Disparities & Health Equity

19 Chapter 18: Perioperative Medicine & Medical Consultation

18.1 Preoperative Cardiovascular Risk Assessment 18.2 Preoperative Pulmonary Risk & Perioperative Medication Management 18.3 Perioperative Anticoagulation, Bridging & Postoperative Complications

20 Chapter 19: Ophthalmology (1% of Exam)

19.1 The Acute Red Eye & Ophthalmic Emergencies 19.2 Painless Vision Loss & Chronic Ophthalmic Disease 19.3 Uveitis, Scleritis & Orbital Disease

21 Chapter 20: Otolaryngology & Dental Medicine (1% of Exam)

20.1 Dizziness, Vertigo & Epistaxis 20.2 Ear Disorders, Hearing Loss & Upper Respiratory Infections 20.3 Oral Cavity, Salivary Gland, Laryngeal & Taste and Smell Disorders

4.9 Fever of Unknown Origin, Neutropenic Fever & Toxic Shock

Key Takeaways Explain This Topic AI

Fever of unknown origin is defined as temperature above 38.3 degrees Celsius on several occasions lasting more than three weeks without diagnosis after appropriate initial investigation.

The three broad categories of classic fever of unknown origin are infection, malignancy and non-infectious inflammatory disease, with a substantial proportion never diagnosed.

Neutropenic fever is a single temperature of 38.3 degrees Celsius or a sustained 38.0 degrees Celsius with an absolute neutrophil count below 500 cells per microliter.

Empiric antipseudomonal beta-lactam monotherapy should begin within one hour of presentation in neutropenic fever.

Staphylococcal toxic shock syndrome is usually culture-negative at the site, whereas streptococcal toxic shock syndrome is typically associated with positive blood cultures and necrotizing soft tissue infection.

Last updated: August 2026

1. Fever of Unknown Origin

ABIM lists fever of unknown origin (FUO) as its own subsection. The classic definition, essentially unchanged since Petersdorf and Beeson, has three components that must all be satisfied:

• Temperature above 38.3 degrees Celsius (101 degrees Fahrenheit) on several occasions
• Duration of more than three weeks

No diagnosis after appropriate initial investigation (historically one week of inpatient workup; now defined by a specified set of ambulatory investigations)

The duration requirement is what makes the differential distinctive. Three weeks excludes essentially all common self-limited viral illness, so the remaining causes are indolent, intermittent or hidden.

The four host categories

• Category Setting Leading causes
• Classic Immunocompetent outpatient Infection, malignancy, non-infectious inflammatory disease

Nosocomial Fever arising after 48 hours in hospital Clostridioides difficile, drug fever, catheter infection, sinusitis, venous thrombosis

• Neutropenic Absolute neutrophil count below 500 Bacterial, then invasive fungal infection
• HIV-associated Advanced HIV Mycobacterium avium complex, tuberculosis, lymphoma, cytomegalovirus
• Causes of classic FUO

Infection — the historically largest group, though its share has fallen with better imaging:

• Extrapulmonary and miliary tuberculosis
• Occult abscess : intra-abdominal, hepatic, pelvic, dental, paraspinal
• Culture-negative endocarditis
• Osteomyelitis , particularly vertebral
• Zoonoses and travel-related infection: brucellosis, Q fever, bartonellosis, typhoid, visceral leishmaniasis

Malignancy :

• Lymphoma — the single most common neoplastic cause
• Renal cell carcinoma; hepatocellular carcinoma; atrial myxoma; leukemia

Non-infectious inflammatory disease — now the largest group in older adults:

Giant cell arteritis and polymyalgia rheumatica — the highest-yield cause of FUO in a patient over 50

Adult-onset Still disease — quotidian spiking fever, evanescent salmon-colored rash, arthralgia, sore throat, and a markedly elevated ferritin

Systemic lupus erythematosus, sarcoidosis, inflammatory bowel disease, vasculitis

Miscellaneous :

Drug fever — occurs at any time after starting a drug, often with relative bradycardia and eosinophilia, and resolves within roughly 72 hours of withdrawal. Common culprits: beta-lactams, sulfonamides, anticonvulsants, allopurinol, heparin.

Venous thromboembolism ; subacute thyroiditis ; familial Mediterranean fever ; factitious fever .

A rational approach

The single most productive intervention is a repeat history and physical examination performed serially, with an exhaustive review of travel, occupational, animal, dietary and sexual exposures and a complete medication list including supplements. Then:

Discontinue every non-essential medication.

Basic laboratory studies including erythrocyte sedimentation rate and C-reactive protein , ferritin, and blood cultures held for fastidious organisms.

Cross-sectional imaging of chest, abdomen and pelvis.

Temporal artery biopsy in patients over 50 with elevated inflammatory markers.

FDG-PET/CT to localize occult inflammation when the above is unrevealing.

Empiric antibiotics are generally the wrong answer in a hemodynamically stable patient with FUO: they obscure cultures without treating the two-thirds of cases that are not infectious. The exception is suspected culture-negative endocarditis or a deteriorating patient.

2. Fever and Neutropenia

Enumerated under bacteremia and sepsis syndrome , and one of the true medical emergencies on the exam.

Definitions:

Fever: a single oral temperature of 38.3 degrees Celsius (101 degrees Fahrenheit) , or 38.0 degrees Celsius (100.4 degrees Fahrenheit) sustained over one hour

Neutropenia: absolute neutrophil count below 500 cells per microliter , or below 1,000 with an expected decline to below 500

The governing principle is that the inflammatory signs of infection are absent because the neutrophils that produce them are absent. There will be no infiltrate on chest radiograph, no purulence, no fluctuance. Fever may be the only sign of overwhelming infection.

Management

Empiric antipseudomonal beta-lactam monotherapy within one hour. Cefepime, piperacillin-tazobactam or a carbapenem. Speed matters more than breadth.

Do not routinely add vancomycin. It is added only for specific indications: hemodynamic instability, suspected catheter-related infection, skin or soft tissue infection, known colonization with resistant gram-positive organisms, or severe mucositis.

Add antifungal coverage for persistent fever beyond four to seven days of appropriate antibacterial therapy.

Avoid digital rectal examination and rectal thermometry , which can seed bacteremia through friable mucosa.

Risk-stratify. Selected low-risk patients with anticipated short neutropenia and no comorbidity may be managed as outpatients on oral therapy.

Typhlitis (neutropenic enterocolitis) presents with right lower quadrant pain, fever and diarrhea in a neutropenic patient; it is managed medically, and surgery is reserved for perforation or uncontrolled bleeding.

3. Toxic Shock Syndrome

A toxin-mediated illness in which a superantigen bypasses normal antigen presentation and activates a large fraction of T cells simultaneously, producing massive cytokine release.

• Staphylococcal TSS Streptococcal TSS
• Organism Staphylococcus aureus (TSST-1) Group A Streptococcus

Classic setting Retained tampon, nasal packing, surgical wound Necrotizing soft tissue infection , varicella, minor trauma

• Blood cultures Usually negative Usually positive
• Local pain Often minimal Severe
• Rash Diffuse macular erythroderma with later desquamation Less prominent
• Mortality Lower Higher

Shared features: fever, hypotension, and multiorgan involvement across at least three systems — renal, hepatic, hematologic, gastrointestinal, mucous membrane, muscular or central nervous system.

Management principles:

Aggressive fluid resuscitation — capillary leak produces enormous fluid requirements.

Source control — remove the tampon or packing; take necrotizing infection to the operating room. Antibiotics alone will not work.

Antibiotics: a beta-lactam plus clindamycin. Clindamycin is essential because it inhibits ribosomal toxin synthesis ; beta-lactams are less effective against a high-density, stationary-phase inoculum (the Eagle effect).

Intravenous immunoglobulin is considered in severe streptococcal disease to neutralize circulating superantigen.

The desquamation of palms and soles occurs one to three weeks after onset and is therefore a retrospective clue, not a diagnostic tool at presentation.