Periodic fever and autoinflammatory syndromes — viva

Opening (must-hit)

"I hold the periodic fever syndromes on a single framework. They are autoinflammatory, meaning they are innate, antigen-independent and without autoantibodies, driven by the inflammasome and interleukin-one-beta. The five I carry are familial Mediterranean fever, PFAPA, mevalonate kinase deficiency, the tumour necrosis factor receptor-associated periodic syndrome, and the cryopyrin-associated periodic syndromes. My first move in every case is to confirm the clockwork pattern with a fever diary and to exclude the mimics, infection and malignancy, before I label the syndrome. Then I match the drug to the pathway: colchicine for familial Mediterranean fever to prevent the amyloidosis, interleukin-one blockade for the cryopyrin spectrum and mevalonate kinase deficiency, etanercept for the tumour necrosis factor receptor-associated periodic syndrome, and corticosteroid-abort with tonsillectomy for the refractory PFAPA." [1][4]

Branch A — The Lebanese child with the abdominal pain and the swollen knee

Examiner: A six-year-old of Lebanese background has two-day attacks of fever with severe central abdominal pain and a tender swollen right knee. Between attacks he is well. His father had a renal transplant for amyloidosis. Candidate: This is familial Mediterranean fever. The short one-to-three-day attacks of fever with serositis, the peritonitis that causes the abdominal pain and the transient non-erosive monoarthritis, the Mediterranean ethnic background, and the family history of amyloidosis, are the classical phenotype. I apply the Livneh criteria and confirm with the MEFV gene testing. The management is lifelong colchicine, which reduces the attacks and prevents the AA amyloidosis that affected his father. I build the amyloidosis surveillance with a regular urinalysis for proteinuria and a serum creatinine from the outset. [3][4]

Branch B — The two-year-old with the clockwork fevers

Examiner: A two-year-old has fevers every five weeks for a year, each with a red inflamed throat, mouth ulcers and tender cervical glands, lasting four days. She is entirely well between attacks. Candidate: This is PFAPA. The clockwork interval, the triad of pharyngitis, aphthous stomatitis and cervical adenitis, the complete wellness between attacks, and the normal growth, are the classical phenotype. But I must exclude the hereditary periodic fevers before I confirm the diagnosis, because the corticosteroid that aborts a PFAPA attack will mask a monogenic disease. The management is the abortive corticosteroid at the start of the attack, and the tonsillectomy for the severe refractory cases. The prognosis is excellent, with the spontaneous resolution over years and no amyloidosis. [7][5]

Branch C — The four-month-old with the rash and the conjunctivitis

Examiner: A four-month-old has had a recurrent urticaria-like rash, fever and conjunctivitis since the first weeks of life. The rash does not respond to antihistamines. Candidate: This is a cryopyrin-associated periodic syndrome. The neutrophilic urticaria-like rash, the conjunctivitis and the onset in early infancy are the signature, and the antihistamine resistance is the bedside clue that the urticaria is autoinflammatory rather than allergic. I assess the severity along the spectrum, with the audiology for the sensorineural deafness, the ophthalmology, and the magnetic resonance imaging of the brain for the chronic aseptic meningitis of the severe neonatal form. The management is the early interleukin-one blockade, because untreated disease causes the irreversible deafness, the chronic meningitis and the amyloidosis. [2]

Branch D — The ten-year-old with the new proteinuria

Examiner: A ten-year-old on colchicine for familial Mediterranean fever has developed new proteinuria on the routine urinalysis. Candidate: This is the AA amyloidosis until proven otherwise. The new proteinuria in a child with familial Mediterranean fever signals the amyloid deposition in the kidneys, and it is the complication that the colchicine is meant to prevent. I check the colchicine adherence first, because the non-adherence is the most common cause of the apparent failure, and I assess the renal function with the serum creatinine and the quantification of the proteinuria. I reinforce the colchicine, and if the disease is genuinely colchicine-resistant I add the interleukin-one blockade with the canakinumab. I refer to nephrology and involve the family in the understanding of the lifelong stakes. [4][8]

Branch E — The wrong first move

Examiner: A colleague plans to diagnose PFAPA on the first attack and start the corticosteroid without further testing. Candidate: I would redirect that. The diagnosis of PFAPA requires a documented clockwork pattern across at least two cycles, the exclusion of the hereditary periodic fevers and the cyclic neutropenia, and the paired acute-phase response that is high during the attack and normal between. Starting the corticosteroid on the first attack, before the hereditary syndromes are excluded, risks masking a monogenic disease such as mevalonate kinase deficiency or familial Mediterranean fever, with the untreated amyloidosis or organ damage. The principle is to confirm the pattern and exclude the mimics before the corticosteroid-abort is tried. [7][1]

Branch F — Matching the therapy to the pathway

Examiner: A child with the tumour necrosis factor receptor-associated periodic syndrome asks why a specific drug was chosen. Candidate: The tumour necrosis factor receptor-associated periodic syndrome is driven by the impaired shedding of the tumour necrosis factor receptor from the TNFRSF1A mutation, so the dysregulated signalling is the tumour necrosis factor pathway. I choose the etanercept, the soluble tumour necrosis factor receptor, because it binds the excess tumour necrosis factor and restores the balance. For the refractory disease I add the interleukin-one blockade, because the interleukin-one pathway is secondarily involved. The same logic, matching the drug to the pathway, governs the colchicine for familial Mediterranean fever and the interleukin-one blockade for the cryopyrin spectrum. [2][1]

Branch G — The sepsis in the child on the biologic

Examiner: A child on the canakinumab for a cryopyrin spectrum disease presents with a fever. How do you tell the flare from the sepsis? Candidate: I cannot reliably tell them apart at the bedside, so I manage it as sepsis until proven otherwise. The interleukin-one blockade impairs the innate response to infection, so a febrile child on the biologic gets the full sepsis assessment, with the cultures and the empiric broad-spectrum antibiotics given without delay, while I observe for the autoinflammatory features. The consequence of a missed sepsis is far worse than a brief course of the unnecessary antibiotics, and the rule is never to assume that a fever in a child on a biologic is an autoinflammatory flare until the sepsis is excluded. [8]