Unusual

Immune System


Diagnosis and reasoning

This infant girl has presented with fever and cervical lymphadenopathy. This is not an unusual presentation in this age group, as any infection in the region drained by the cervical lymph nodes can give rise to this clinical picture. Other important (but far less common) possibilities are hematological malignancies, connective tissue disorders, and Kawasaki disease.


The high fever and short duration of symptoms make malignancies and connective tissue disorders less likely (unless a superimposed infection is present). The lack of improvement with antibiotics favors a non infectious etiology (although it might be that the antibiotics were inappropriate).


The examination provides several important clues: cracked lips, and erythematous and indurated palms and soles. When considered along with the cervical lymphadenopathy, 3 of the 5 principal clinical criteria for Kawasai disease are present – not enough to establish the diagnosis, but enough to raise consideration of this possibility

. Toxic shock syndrome, scalded skin syndrome, and toxic epidermal necrolysis can also present in this manner, but affected children are usually far more ill.


Her full blood count shows a neutrophil leukocytosis. This is significant, as lymphocytes are the predominant leukocyte type at this age. While this could be due to both infection or Kawasaki disease, the co-existing thrombocytosis favors the latter. Furthermore, anteroposterior and lateral x-rays of the neck show no soft tissue changes suggestive of pharyngitis or a retro-pharyngeal abscess; and a septic screen is negative. This is more evidence against infection.


Given the increasingly strong possibility of Kawasaki disease, echocardiography should follow, aiming to see if there are any coronary artery abnormalities. This reveals changes suggestive of coronary ateritis. When considered along with the duration of fever and presence of 3 principle clinical findings, this is sufficient to diagnose "atypical" Kawasaki disease.


She should be immediately started on the combination of intravenous immunoglobulin (IVIG) and high-dose acetylsalicylic acid (ASA), to control the inflammation and prevent coronary artery aneurysm formation. There is little value in continuing antibiotics; as ASA itself is an analgesic, there is little value in prescribing acetaminophen (paracetamol) as well.

Discussion

Kawasaki disease is an acute childhood vasculitis that shows a predilection for the coronary arteries; in the developed world, it is the most common cause of acquired heart disease in children. The majority of cases are in children <5 years of age, with a ~1.5:1 male to female ratio. Around 1% of patients have a family history, while there is an increased incidence in siblings of affected individuals and an increased concordance rate in identical twins.


The underlying pathophysiology is unclear; a popular hypothesis is that an undiscovered infectious etiology could be a trigger, with older individuals having natural immunity to this pathogen.


Children with Kawasaki disease present with fever, which is typically high and remittent. There are five other principal clinical findings:

  1. Cervical lymphadenopathy, with multiple non-tender lymph nodes >1.5 cm in diameter.
  2. An erythematous rash that is often diffuse and maculopapular (and not vesicular).
  3. Conjunctivitis that is bilateral, non exudative, and painless.
  4. Oral changes, including injection of the oral and pharyngeal mucosa, dry and cracked lips, and a strawberry tongue.
  5. Changes in the extremities, including erythema, swelling, and desquamation of the palms and soles.

The above clinical findings do not appear simultaneously, but evolve over the course of the illness. Other potential findings include athropathy (potentially leading to misdiagnosis as rheumatic fever) and hepatomegaly.


Kawasaki disease is a clinical diagnosis. For the diagnosis to be made, at least 4 of the 5 principal clinical findings listed above should be present, along with at least 5 days of fever. If all 5 principal clinical findings are present, the diagnosis can be made with only 4 days of fever. Children who do not meet sufficient clinical criteria, but who subsequently are found to have coronary artery abnormalities on imaging can be considered to have “atypical” Kawasaki disease.


All children with diagnosed or suspected Kawasaki disease should receive an echocardiogram. Aneurysms of the coronary arteries are the classical finding, but are rare before 10 days of illness. Prior to this, the presence of coronary arteritis may be suspected by the presence of perivascular brightening, cuffing and absence of the arterial tapering.


As echocardiography has limited ability to visualize disease of the distal coronary arteries, computed tomography (CT) and magnetic resonance imaging (MRI) may be considered in certain cases. While coronary angiography is the gold standard for assessment of the coronary circulation, it is invasive, and is not performed routinely. ECGs may be helpful for detection of myocarditis, pericarditis, or myocardial ischemia.


With respect to basic investigations, elevated inflammatory marker levels and a neutrophil leukocytosis are typical findings. Both thrombocytosis and thrombocytopenia may occur; patients with the latter generally have a more difficult clinical course. Elevations of transaminases, gamma-glutamyl transferase, and bilirubin may be seen. Levels of albumin, sodium and hemoglobin may be decreased. Sterile pyuria may occur due to the presence of urethritis or meatitis.


The treatment of Kawasaki disease can be broadly classified into treatment of the acute phase and treatment following resolution of systemic inflammation. Treatment of the acute phase is accomplished by administering a single dose of IVIG paired with high-dose ASA. This combination greatly reduces the incidence of coronary artery aneurysms. A reduction in fever typically indicates response to treatment; conversely, prolonged fever indicates resistance to treatment.


Patients who do not show a sufficient response the above regimen often respond to a second dose of IVIG. Options in refractory disease include iv corticosteroids, cyclosporine, cyclophosphamide, infliximab and other monoclonal antibodies, and plasma exchange.


After the acute phase, low-dose ASA should be given prophylactically for a duration of 6-8 weeks, so as to prevent coronary artery thrombosis. In children with aneurysms, long-term aspirin therapy may prove to be necessary. If giant aneurysms are present, anticoagulation with low-molecular-weight heparins (LMWH) or warfarin is indicated to prevent coronary artery thrombosis.


Where there is coronary artery stenosis due to thrombotic activity or regression of luminal dimension at the beginning or ending points of the aneurysm, procedures such as balloon angioplasty, stenting, or coronary artery bypass grafting may be indicated in the long run.

Take home messages

  1. Kawasaki disease is a clinical diagnosis.
  2. "Atypical" Kawasaki disease can be diagnosed in patients who do not meet the clinical criteria, if imaging evidence of coronary artery disease is present.
  3. The combination of ASA and IVIG is key to reducing the risk of aneurysm formation.

References

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