Tuesday, 24 December 2019

P KD X MAS

Nightly Fever, Swollen Lymph Nodes, and Rash in a 3-Year-Old

Sarah Taber, MD
December 16, 2019
Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please contact us.

Background

A 3-year-old boy with no significant past medical history presented to the emergency department (ED) with 10 days of nightly fever. He also had cervical lymphadenopathy and an intermittent erythematous macular rash similar to the one shown below.
His parents also stated that he exhibited pain bilaterally in his knees, ankles, and hips. Before the onset of the fevers, he had been well. His parents reported no other symptoms, including conjunctivitis, oral mucosal changes, hand or foot swelling, rhinorrhea, cough, dyspnea, abdominal pain, vomiting, or diarrhea. He had no known sick contacts. His parents reported no travel outside the United States. The family has no pets. He has one older brother, who is healthy. The parents reported no relevant family history.

Physical Examination and Workup

Upon examination, the patient was febrile and irritable, with large, palpable cervical lymph nodes. He had swelling of his bilateral knees and ankles and was reluctant to bear weight. His abdomen was diffusely tender to palpation, and he had mild hepatosplenomegaly. He had an erythematous macular rash, which displayed the Koebner phenomenon.
His CBC was significant for leukocytosis, thrombocytosis, and anemia for his age. His laboratory findings also showed an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein, alanine aminotransferase, and aspartate aminotransferase (AST) levels. He had negative blood culture, respiratory viral panel, and other infectious study findings. His echocardiography findings were normal. Abdominal ultrasonography confirmed the hepatosplenomegaly but was otherwise normal.
On the basis of his history, as well as physical examination and laboratory findings, the patient was diagnosed with incomplete Kawasaki disease (KD) and admitted for treatment. He received standard therapy with intravenous immunoglobulin (IVIG) at 2 g/kg and aspirin. However, more than 36 hours after treatment, he still had nightly fevers. He was treated with another dose of IVIG. Although he remained febrile, his laboratory findings appeared to improve. His white blood cell count, platelet count, and ESR all began to decrease. However, his cell counts did not stabilize once they reached normal levels. Within 24 hours, the patient became leukopenic, thrombocytopenic, and more anemic than he was at initial presentation. His transaminitis worsened. Further laboratory workup revealed a low fibrinogen level, prolonged prothrombin time, and partial thromboplastin time, and a ferritin level > 10,000 ng/L. The patient became lethargic, with worsening rash and unremitting fever.
Which of the following is the most likely diagnosis?
Your Peers Chose:

Discussion

Macrophage activation syndrome (MAS) is a severe and potentially fatal immune phenomenon characterized by overactivation and proliferation of macrophages and T cells. It is closely related to hemophagocytic lymphohistiocytosis (HLH), a similar diagnosis that may occur as a result of genetic factors or certain malignancies. HLH and MAS are thought to exist along a spectrum, and MAS has been described as a type of secondary HLH that occurs in patients with an underlying rheumatologic disorder. Although most closely associated with systemic-onset juvenile idiopathic arthritis (SoJIA), MAS is also associated with numerous other rheumatologic diseases, including systemic lupus erythematosus and KD.
Patients with MAS have characteristic laboratory findings, including low cell counts, ESR, and fibrinogen levels, along with elevated liver function test results, coagulation test findings, and ferritin levels. Clinical manifestations include bleeding, hepatosplenomegaly, unremitting fevers and rash, lethargy, seizures, coma, and death.[1]
Criteria for MAS complicating SoJIA state that a febrile patient with known or suspected SoJIA is classified as having MAS if they have a ferritin level ≥ 684 ng/L, in addition to two of the following:[2]
  • Platelet count ≤ 181 × 109/L
  • AST level > 48 U/L
  • Triglyceride level > 156 mg/dL
  • Fibrinogen level ≤ 360 mg/dL
A diagnostic tool has also been developed to distinguish MAS from primary HLH.[3] Patients with primary HLH tend to be younger (age at onset, ≤ 1.6 years) with more pronounced neutropenia, anemia, and thrombocytopenia; lower fibrinogen level; and a higher likelihood of splenomegaly.
MAS is associated with numerous rheumatologic disorders, but it is most closely associated with SoJIA. SoJIA, formerly called Still disease, is an autoinflammatory disorder that is characterized by arthritis and extra-articular manifestations, including fevers, rashes, lymphadenopathy, and serositis. The typical rash of SoJIA is described as an "evanescent salmon-pink rash." It also shows the Koebner phenomenon, which is the propensity to appear on areas of minor trauma, such as a light scratch. SoJIA may present at any age; in patients aged 18 years and older, it is referred to as adult-onset Still disease.
Other disorders, such as infection or malignancy, may mimic SoJIA. These must be excluded before the diagnosis is made. To receive a definitive diagnosis of SoJIA, a patient must have fevers for at least 2 weeks and arthritis for 6 weeks; however, in individuals with a characteristic presentation, a preliminary diagnosis can be made before that, and treatment can be initiated. MAS can occur at any point in patients with SoJIA, including at presentation, and may also be triggered by treating the disease.
Although MAS may occur in KD, its development should prompt physicians to consider whether the underlying diagnosis may actually be SoJIA. Distinguishing between SoJIA and KD can be difficult, because the two disorders share many features. One clue is the pattern of the fevers; patients with KD tend to be constantly febrile, whereas patients with SoJIA have quotidian fevers that typically occur nightly. Patients with SoJIA also often have more generalized lymphadenopathy and may have hepatosplenomegaly, which is not typically seen in KD. In addition, conjunctivitis and oral mucosal changes, which are diagnostic criteria for KD, are not usually seen in SoJIA.
Acute MAS shares many features with sepsis, and potential infectious sources must be ruled out before diagnosing or treating MAS. MAS may also closely resemble hematologic malignancies. In some cases, a bone marrow biopsy is required to rule out an underlying cancer. In this case, the patient underwent further workup, including blood, urine, and cerebrospinal fluid cultures; viral studies; and a bone marrow biopsy. His infectious workup was negative, and his biopsy did not show any signs of malignancy, although he did have hemophagocytosis consistent with MAS.
Regardless of the cause, MAS represents a medical emergency that must be urgently recognized and treated to prevent serious or fatal sequelae. The initial treatment of MAS typically consists of intravenous methylprednisolone pulse therapy (30 mg/kg/dose), followed by oral prednisone. In patients who do not have an adequate response to steroids, cyclosporine A and, more recently, anakinra (a recombinant interleukin-1 receptor antagonist) have been used successfully.[1,4] Etoposide, which is a mainstay of treatment for primary HLH, is not typically used in MAS, except for in highly refractory cases.
The patient in this case was treated with 3 days of intravenous methylprednisolone (30 mg/kg/dose), as well as anakinra (100 mg/day). Within 48 hours of initiating therapy, his fevers abated and his laboratory findings began to improve. After several days of therapy, he was discharged home on oral prednisone and daily anakinra. Although his systemic symptoms resolved, he developed persistent arthritis in several joints as his prednisone was being weaned. His final diagnosis was SoJIA presenting with MAS, which was initially misdiagnosed as KD.

Question 1 of 2

Which of the following is most accurate about SoJIA and MAS?
Your Peers Chose:
MAS is a severe and potentially fatal immune phenomenon that can occur as a complication of numerous rheumatologic diseases, most prominently SoJIA. It is closely related to HLH; however, HLH occurs because of genetic factors or certain malignancies, whereas MAS occurs secondary to rheumatologic disease. MAS may occur at any time in a patient with SoJIA and may be triggered by treatment for the disease. For a definitive diagnosis of SoJIA, patients must have fevers for 2 weeks and arthritis for 6 weeks; however, in patients with characteristic symptoms, particularly those with MAS on presentation, treatment can (and should) be initiated before this time.

Question 2 of 2

Which of the following is a recognized criterion for MAS complicating SoJIA?
Your Peers Chose:
Criteria for MAS complicating SoJIA state that a febrile patient with known or suspected SoJIA is classified as having MAS if they have a ferritin level ≥ 684 ng/L, in addition to two of the following:
  • Platelet count ≤ 181 × 109/L
  • AST level > 48 U/L
  • Triglyceride level > 156 mg/dL
  • Fibrinogen level ≤ 360 mg/dL

References

  1. Minoia F, Davì S, Horne A, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014;66:3160. Source
  2. Ravelli A, Minoia F, Davì S, et al. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2016;75:481-489. Source
  3. Minoia F, Bovis F, Davì S, et al. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primarily hemophagocytic lymphohistiocytosis from macrophage activation syndrome. J Pediatr. 2017;189:72. Source
  4. Rajasekaran S, Kruse K, Kovey K, et al. Therapeutic role of anakinra, an interleukin-1 receptor antagonist, in the management of secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction/macrophage activating syndrome in critically ill children. Pediatr Crit Car Med. 2014;15:401-408. Source
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