Reactive Mesenteric Lymphadenopathy (Mesenteric Adenitis)

Definition

• Bailey and Love's Short Practice of Surgery, 28th Ed.

Pathophysiology

• They receive lymphatic drainage from the terminal ileum and proximal colon
• This region has the highest density of gut-associated lymphoid tissue (GALT) in the body

Aetiology / Causative Organisms

• Bailey and Love's Short Practice of Surgery, 28th Ed.
• Goldman-Cecil Medicine International Edition
• Harrison's Principles of Internal Medicine, 22nd Ed.

Clinical Features

In Children (non-specific mesenteric adenitis)

• Most common in children and teenagers - this is the typical demographic
• Short attacks of central abdominal pain lasting 10-30 minutes
• Commonly associated with vomiting
• Patient often does not look severely ill
• Fever in >50% of cases (often markedly elevated)
• Poorly localised abdominal tenderness
• Shifting tenderness - a valuable sign distinguishing it from appendicitis (the point of maximum tenderness shifts when the patient is repositioned)
• May have enlarged cervical, axillary, or inguinal lymph nodes (look for these)
• History of recent upper respiratory tract infection is common

In Adults

• Yersinia infection in adults tends to present as terminal ileitis or mesenteric adenitis rather than ileocolitis
• Can cause arthritis, cellulitis, erythema nodosum, and septicaemia as complications
• Those with underlying conditions (diabetes, cirrhosis, haemochromatosis) are at higher risk of complicated disease
• Bailey and Love's Short Practice of Surgery, 28th Ed.
• Pye's Surgical Handicraft, 22nd Ed.
• Sleisenger and Fordtran's GI and Liver Disease

Diagnosis and Investigations

Laboratory

• Leukocytosis 10,000-12,000/µL (10-12 × 10⁹/L) on day 1 of the attack - characteristically falls on day 2 (this pattern can help distinguish it from appendicitis, where WBC typically stays elevated)

Imaging

• Ultrasonography - first-line, helpful in differentiating from appendicitis; shows clusters of enlarged mesenteric lymph nodes (>5 mm short axis)
• CT scan - more sensitive for confirming lymphadenopathy, excluding appendicitis, and identifying complications; can show right lower quadrant reactive mesenteric lymphadenopathy clearly
• In some cases, exploratory laparoscopy is needed - at which point a normal appendix alongside enlarged nodes clinches the diagnosis
• Bailey and Love's Short Practice of Surgery, 28th Ed.

Key Differential Diagnosis: Mesenteric Adenitis vs Acute Appendicitis

• Schwartz's Principles of Surgery, 11th Ed.
• Maingot's Abdominal Operations

Intussusception Connection

• Current Surgical Therapy, 14th Ed.

Yersinia and Pseudoappendicitis Syndrome

• Harrison's Principles of Internal Medicine, 22nd Ed.
• Yamada's Textbook of Gastroenterology, 7th Ed.
• Jawetz, Melnick & Adelberg's Medical Microbiology, 28th Ed.

Association with Other Conditions

• Celiac disease - active celiac disease commonly causes mesenteric lymphadenopathy (and even cavitating mesenteric lymph nodes - "cavitating mesenteric lymph node syndrome")
• Crohn's disease - ileocaecal mesenteric adenitis occurs in ileocolic Crohn's; the mesentery becomes thickened, shortened, and oedematous ("fat wrapping" or "creeping fat")
• Tuberculosis - can cause mesenteric lymphadenopathy with caseating granulomas
• AIDS/HIV - Mycobacterium avium intracellulare infection commonly causes wall thickening and mesenteric lymphadenopathy at the proximal small intestine
• Whipple's disease - low-density mesenteric lymphadenopathy due to lipid deposition
• Lymphoma (EATL) - can present with mesenteric lymphadenopathy with central cavitation

Treatment

Viral Mesenteric Adenitis

• Supportive treatment - analgesia, hydration, rest
• Resolves spontaneously but can recur

Bacterial Mesenteric Adenitis (e.g. Yersinia, Campylobacter)

• Symptoms include cramping pain, vomiting, and diarrhoea
• Can be severe and require hospitalisation
• Antibiotics appropriate for confirmed bacterial aetiology (e.g. Yersinia: trimethoprim-sulfamethoxazole or fluoroquinolones in severe/extraintestinal disease)
• Bailey and Love's Short Practice of Surgery, 28th Ed.

Summary

Recurrent Monthly Fever with Chills/Rigors in an Adult

How to Think About This: Fever Patterns

"Some infections have characteristic patterns in which febrile episodes are separated by intervals of normal temperature... In the Pel-Ebstein pattern, fever lasting 3-10 days is followed by afebrile periods of 3-10 days; this pattern can be classic for Hodgkin disease and other lymphomas. In cyclic neutropenia, fevers occur every 21 days and accompany the neutropenia. There are also a number of periodic fever syndromes (e.g., familial Mediterranean fever, TRAPS) that differ in their periodicity, duration of attack, and constellation of clinical features."

Differential Diagnosis - Structured by Category

1. INFECTIOUS CAUSES

Malaria (Top priority if any travel history or endemic exposure)

• P. vivax and P. ovale are the most important in the context of monthly recurrences - their dormant liver stage (hypnozoites) can reactivate weeks to months after the original infection, causing clinical relapse with full rigors and fever even after the initial illness has resolved.
• Ask specifically about: travel history, mosquito exposure, previous malaria treatment (was primaquine given to clear the liver stage?).
• Medical Microbiology 9e; Harrison's Principles of Internal Medicine, 22nd Ed.

Brucellosis ("Undulant Fever")

• Classic name "undulant fever" reflects its remittent, relapsing character
• Almost all patients have fever, which is intermittent in untreated patients
• Associated with: livestock contact, unpasteurised dairy products, abattoir workers
• Multi-system involvement: joints, liver, reproductive organs, CNS
• Harrison's Principles of Internal Medicine, 22nd Ed.; Medical Microbiology 9e

Relapsing Fever (Borrelia spp.)

• Borrelia recurrentis (louse-borne) or tick-borne Borrelia spp.
• Pattern: days of fever → several-day afebrile interval → relapse
• Rigors are prominent
• Ask about tick exposure or travel to endemic areas

Tuberculosis (extrapulmonary/miliary)

• Typically a more continuous low-grade fever but can have a relapsing component
• Hepatic TB, miliary TB, and TB in immunocompromised patients can present as FUO

Other infections to consider

• Visceral leishmaniasis (Kala-azar) - irregular fever, splenomegaly, weight loss
• Infective endocarditis - culture-negative forms can cause periodic fever-like episodes
• Occult abscess - (hepatic, splenic, subphrenic) - most common infectious cause of FUO overall

2. NON-INFECTIOUS INFLAMMATORY / AUTOINFLAMMATORY CAUSES

Familial Mediterranean Fever (FMF)

• Autosomal recessive, most common in people of Mediterranean/Middle Eastern ancestry
• Recurrent episodes of fever + abdominal pain + inflammatory arthritis + serositis
• Episodes last 1-3 days and resolve completely between attacks
• Classic clinical picture: Lebanese/Armenian/Turkish descent, recurrent since childhood
• Treatment: colchicine (prevents attacks and prevents amyloidosis)
• Frameworks for Internal Medicine; Fitzpatrick's Dermatology

TRAPS (TNF Receptor-Associated Periodic Syndrome)

• Autosomal dominant
• Fever episodes lasting 3 weeks or longer (longer than FMF)
• Accompanied by abdominal pain, myalgia, skin lesions (migratory erythema)
• Skin lesions are characteristic and help differentiate from FMF
• Fitzpatrick's Dermatology; Harrison's Principles of Internal Medicine, 22nd Ed.

Adult-Onset Still's Disease (AOSD)

• Systemic inflammatory disorder, bimodal age peaks: 15-25 and 36-46 years
• Quotidian fever (≥39°C, one or two peaks daily) - but can have recurring episodic bouts
• Characteristic salmon-colored evanescent rash that appears with fever and disappears when afebrile
• Markedly elevated ferritin (often >2000 ng/mL) - a key diagnostic clue
• Pharyngitis, arthralgias/arthritis
• Presents as FUO in up to 10% of cases
• Treatment: glucocorticoids first-line
• Frameworks for Internal Medicine

Hyperimmunoglobulinemia D Syndrome (HIDS / Mevalonate Kinase Deficiency)

• Autosomal recessive, primarily northern European ancestry
• Mutations in mevalonate kinase (MVK) gene
• Recurrent fever episodes

Systemic Lupus Erythematosus (SLE)

• Episodic flares with fever, multi-system features
• More common in women of reproductive age
• Key labs: ANA, anti-dsDNA, low complement (C3/C4)

3. MALIGNANT CAUSES

Hodgkin Lymphoma - Pel-Ebstein Fever

• Pel-Ebstein fever: fever lasting 3-10 days, followed by afebrile periods of 3-10 days - a pattern highly characteristic of Hodgkin's disease
• Fever is high and spiking
• Associated symptoms: night sweats, weight loss, pruritis (intense itching at night is a helpful clue), painless lymphadenopathy
• Harrison's Principles of Internal Medicine, 22nd Ed.; S Das Manual on Clinical Surgery

Other Lymphomas and Leukemias

• Non-Hodgkin lymphoma, leukemia, multiple myeloma can all present with FUO-type intermittent fever
• Often associated with macrocytosis, lymphadenopathy, hepatosplenomegaly

Renal Cell Carcinoma

• Classic triad: haematuria, flank pain, palpable mass - but many present with fever alone
• Consider in a middle-aged man with smoking history, hematuria, polycythemia

Diagnostic Approach

History - Key Questions

• Travel history to malaria-endemic areas? (any time in the past, not just recently for vivax)
• Previous malaria infection and treatment - was primaquine given?
• Animal contact (livestock, unpasteurised dairy) → brucellosis
• Night sweats, weight loss, pruritis → lymphoma
• Ethnicity and family history of periodic fever → FMF/TRAPS
• Tick exposure → relapsing fever
• Immunosuppression, HIV status

Examination

• Lymphadenopathy (generalised or localised)
• Splenomegaly (malaria, brucellosis, leishmaniasis, lymphoma)
• Hepatomegaly
• Skin rash (AOSD salmon rash; TRAPS migratory erythema)
• Relative bradycardia with fever (brucellosis, typhoid, leptospirosis)

Investigations (Stepwise)

Summary Table: Distinguishing Features at a Glance

Revised Differential - Monthly Fever, Normal CBC & CRP, No True Rigors

• No ongoing infection or chronic inflammation
• No haematological malignancy actively suppressing or stimulating the marrow
• The episodes are likely self-contained bursts with full inter-episode recovery

Top Differential Now

1. PFAPA Syndrome (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis)

• Fever episodes occurring at regular ~monthly intervals (every 3-8 weeks)
• Each episode lasts 3-7 days, then resolves completely
• Accompanied by one or more of: sore throat/pharyngitis, mouth ulcers (aphthous), cervical lymphadenopathy
• Completely well between episodes - normal CRP, normal CBC between attacks
• During attacks, inflammatory markers (CRP, ESR, WBC) rise then normalise
• Negative throat cultures (not bacterial)
• Key diagnostic test: single dose of prednisolone (1 mg/kg) aborts the episode dramatically within hours - this response is both diagnostic and therapeutic
• Tonsillectomy can be curative in refractory cases

• Tintinalli's Emergency Medicine; Schwartz's Principles of Surgery, 11th Ed.
• Frontiers in Immunology PFAPA diagnostic criteria

2. Cyclic Neutropenia

• Fever recurring predictably every ~21 days, lasting 3-5 days
• CBC is normal between episodes but WBC (especially neutrophils) plummets during the episode
• This is the critical point: a normal CBC checked between attacks does NOT rule this out
• Must check CBC during the febrile episode to catch the neutropenia
• Neutrophil count <500/mm³ during the attack, recovering rapidly after
• Often accompanied by mouth sores, mild pharyngitis, occasionally lymphadenopathy
• Bone marrow biopsy during neutropenia shows myeloid maturation arrest
• Treatment: granulocyte colony-stimulating factor (G-CSF) in severe cases

• Harrison's Principles of Internal Medicine, 22nd Ed.

3. Familial Mediterranean Fever (FMF) - attenuated

• Most episodes in FMF are accompanied by a CRP spike, but some patients (particularly with milder mutations) can have incomplete phenotype with fever alone
• The inter-episode interval is typically 4-6 weeks (fits monthly pattern)
• Between attacks: completely normal inflammatory markers - this is characteristic of FMF
• Look for: Mediterranean/Middle Eastern/Armenian/Turkish ethnicity, family history, associated abdominal pain, arthralgia, or chest pain (may be subtle or absent in adults)
• Genetic testing: MEFV gene mutation confirms diagnosis
• Trial of colchicine is both diagnostic and therapeutic - most patients respond well

4. Physiological / Menstrual-Cycle-Related Fever

• Ovulatory fever - mild temperature rise at mid-cycle (normal physiology, progesterone effect)
• Premenstrual fever - luteal phase temperature elevation
• Catamenial syndromes - including catamenial pneumothorax or endometriosis-related fever around menstruation
• Ask: Does the fever correlate with menstrual cycle timing?

5. Factitious Fever / Thermometer Manipulation

• Must be considered whenever fever is reported but inflammatory markers are consistently normal
• Typically affects healthcare workers, individuals with psychological disorders (Munchausen syndrome/Factitious Disorder Imposed on Self)
• Clues: no diaphoresis with fever, normal pulse-temperature relationship, fever disappears when observed, inconsistent thermometer readings
• Check: rectal/witnessed temperature, urine temperature (most reliable), temperature-pulse dissociation

6. Occult Viral Reactivation

• EBV reactivation - can cause recurrent low-grade fever with fatigue, minimal inflammatory response
• CMV - similar pattern especially in mildly immunocompromised individuals
• HHV-6 reactivation
• These typically produce a very mild or absent CRP response
• Check: EBV VCA IgM/IgG, monospot, CMV serology

7. Thyroid Dysfunction / Hyperthyroidism

• Hyperthyroidism can cause persistent low-grade fever and feeling of recurrent heat/warmth
• Sometimes misinterpreted as intermittent fever
• Check: TSH, free T4

Revised Investigations - Prioritised for This Pattern

Critical Next Step