A teenage female with fever, weight loss, malar rash, joint pain, and hair fall

Discussion of the case

The adolescent female presented with the following symptoms: fever, anemia requiring blood transfusion, weight loss of more than 7 kgs in a one-month, malar rash, and hair fall. Previous investigations indicated persistently low hemoglobin, leucocytosis, elevated platelet count, ESR, and CRP. PET-CT results showed insignificant lymph nodes, whereas fine needle aspiration cytology (FNAC) indicated reactive adenitis. ANA and RF were negative.

The possible differential diagnoses are infection, malignancy especially hematological, and autoimmune disease. The factors that suggest the possibility of having an infectious etiology are the short duration of disease, younger age group, significant weight loss, and elevated inflammatory parameters including total count and increased neutrophil count. In the absence of localizing signs and if the infection extends beyond 4 weeks and not responding to anti-bacterial, the possibility of sub-acute bacterial endocarditis, abdominal infections, tuberculosis, or prolonged viral infection should be considered.  The possibility of hematological malignancy could be ruled out since the count was not significantly elevated, and the findings of differential and peripheral smear examinations were negative for leukemia. Another probability is lymphoma, especially non-Hodgkin lymphoma. PET-CT performed before referral showed a few insignificant lymph node enlargements and FNAC results indicated reactive adenitis changes. The autoimmune diseases to be considered are systemic-onset juvenile chronic arthritis, sJIA), SLE, and related connective tissue diseases. Although negative ANA, normal complement and elevated CRP contradict the probability of SLE, the presence of malar rash and excess hair fall favor the diagnosis. In the pediatric population, fever and lymphadenopathy are the often-dominating clinical features of SLE. These exclusions increase the possibility of having Still's disease, but the presence of persistent fever and the lack of typical rash associated with high fever are contradictory to the possible diagnosis of Still's.

sJIA is defined by the presence of joint pain in one or more joints along with spiking fever (a typical daily high fever with a spike in the evening) for a minimum of 15 days, with at least one of the following clinical manifestations: skin rash (an evanescent, non-fixed erythematous rash that accompanies fever spikes), generalized lymphadenopathy, hepatomegaly and/or splenomegaly, or serositis (pleuritis or pericarditis). However, none of the clinical features is specific to sJIA, especially at the initial presentation. Hence differential diagnosis is challenging and needs to carefully exclude bacterial, and viral infections, malignancy, and other rheumatic diseases. In certain cases, arthritis may be absent at onset and can develop during the disease course, often progressing to a polyarticular and symmetrical involvement.^[1] Per the International League Against Rheumatism (ILAR) criteria, arthritis is necessary to classify a patient as having sJIA (Table 1).  Hence strict adherence to the ILAR criteria may lead to an unacceptable delay in diagnosis. This may lead to increased mortality and morbidity in sJIA patients. One of the recent studies from India has reported the absence of arthritis in a good proportion of children fulfilling the criteria of Still's disease.^[2]

Table 1: Comparison of the features of the ILAR and Yamaguchi criteria

*Typical rash = Nonpruritic macular or maculopapular salmon-colored rash (usually over trunk or extremities while febrile).

Fluorodeoxyglucose PET/CT is one of the useful tools in detecting pyrexia of unknown origin (PUO), but it may fail in 10-20% of patients.^[5] The PET/CT performed on the child excluded the possibility of having a localized infection or proliferating tumor. Although the presence of active lymph nodes was very few, FNAC results indicating reactive adenitis raise the possibility of non-malignant disease.

The result of the blood culture positive for S. aureus was later identified as contamination. Screening for possible endocarditis by ECHO and other criteria was negative. Persistently elevated inflammatory parameters including the total count indicate a non-infectious and non-malignant etiology.

Serum ferritin often can help to differentiate infections and certain autoimmune diseases. The four most common immune-mediated conditions associated with high ferritin levels are macrophage activation syndrome (MAS), Still's a disease (AOSD), catastrophic antiphospholipid syndrome (cAPS), and septic shock. ^[6] In a study that identified elevated serum ferritin levels in 89% of the patients, the levels were five times greater than normal in nearly half of the subjects.^[7] However, it is not pathognomonic for Still's disease. In the current case serum ferritin was not significantly high (two times greater than the cut-off).

Diagnosis of PUO is a challenge if no localized signs are present. Fever of unknown origin may be caused by infectious diseases, malignancies, collagen vascular diseases, or a variety of miscellaneous disorders. In patients above 50 yrs, the preponderance of PUO is attributable to neoplastic and infectious etiology; whereas, collagen vascular diseases, neoplasms, and viral infections predominate in children. Careful analysis of the history, physical findings, and laboratory tests is important for diagnosing PUO. Direct diagnostic workup is recommended in PUO patients showing localized signs over some time. The most perplexing is identifying the cause of PUO in patients without specific diagnostic tests, e.g., juvenile rheumatoid arthritis (JRA) or adult Still's a disease.

Final Diagnosis

The patient developed joint pain within a few weeks during follow-up, thereby fulfilling the criteria. However, the clinical diagnosis of Still's was made before developing the joint pain.

Learning point

1. Careful exclusion of differential diagnoses is essential for Still's disease
2. Persisting leucocytosis in an otherwise not very sick child one should consider Stills

References

1. Rossi-Semerano L, Kone-Paut I. Is Still's Disease an Autoinflammatory Syndrome? International journal of inflammation. 2012;2012:480373.
2. Kumar S, Kunhiraman DS, Rajam L. Application of the Yamaguchi criteria for the classification of "suspected" systemic juvenile idiopathic arthritis (sJIA). Pediatric rheumatology online journal. 2012;10(1):40.
3. R. E. Petty, T. R. Southwood, P. Manners, et al., "International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, edmonton, 2001," Journal of Rheumatology, vol. 31, no. 2, pp. 390–392, 2004.
4. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al: Preliminary criteria for the classification of adult Still's disease. J Rheumatol 1992, 19:424–430
5. Seshadri N, Sonoda LI, Lever AM, Balan K. Superiority of 18F-FDG PET compared to 111In-labelled leucocyte scintigraphy in the evaluation of fever of unknown origin. The Journal of infection. 2012;65(1):71-9.
6. Rosario C, Zandman-Goddard G, Myron-Holtz EG, D'Cruz DP, Shoenfeld Y. The hyperferritinemia syndrome: macrophage activation syndrome, Still's a disease, septic shock, and catastrophic antiphospholipid syndrome. BMC medicine. 2013;11:185.
7. Uppal SS, Al-Mutairi M, Hayat S, Abraham M, Malaviya A. Ten years of clinical experience with adult-onset Still's disease: is the outcome improving? Clinical rheumatology. 2007;26(7):1055-60.