Fever of Unknown Origin in a 17-Year-Old Girl

Fever of unknown origin (FUO) is defined as fever (>101°F) that lasts more than three weeks and for which a cause is not found within seven days of hospital evaluation. FUO has a broad list of differentials - infection, inflammatory diseases, and malignancy. A detailed history and meticulous clinical examination with thorough and stepwise investigations lead to a diagnosis in only two-thirds of cases. In this article, we present a 17-year-old adolescent girl, with no significant past medical history, who presented with FUO during the COVID pandemic. A high index of suspicion and extensive investigations revealed the final diagnosis.


Introduction
With hundreds of potential causes, FUO is challenging for physicians. In recent times, COVID-19 has been recognized as a cause of persistent fever [1].
During the peak of the COVID-19 pandemic, a 17-year-old adolescent girl presented with high fever for three weeks and was suspected of having multisystem inflammatory syndrome in children (MIS-C) after initial laboratory tests. She tested negative for polymerase chain reaction (PCR) COVID-19 multiple times. Although it is well-known that PCR COVID-19 can be negative in children with MIS-C [2][3], a search for an alternate cause led to the final diagnosis.

Case Presentation
A 17-year-old adolescent girl with no significant past medical history presented to the emergency room with complaints of a high fever (102-103°F), sore throat, headache, watery diarrhea, dizziness, and palpitations for the past three weeks. She denied cough, shortness of breath, joint pains, skin rashes, night sweats, history of recent travel, exposure to sick contacts, or illicit drug use.
Her mother reported anorexia with an unintentional weight loss of 8 pounds during this period. The patient had an emergency room visit for left knee pain three months prior, which had subsequently improved with analgesics. All immunizations were up to date except for the annual influenza vaccine.
There were no rashes, joint swelling, tonsillar exudates, organomegaly, heart murmur, or added sounds upon lung examination. The initial laboratory findings are summarized in Table 1.  During the next two weeks, our patient continued to have a high fever of up to 103-104°F. All workup for common and atypical infections, which included Cytomegalovirus, Adenovirus, Epstein Barr, Lyme, Streptococcal, Brucella, Mycoplasma, Legionella, Erchilicia, Tuberculosis, HIV, Cryptococcus, and COVID-19, were negative. The CT scan of the chest and abdomen with contrast was normal. A bone marrow aspirate and biopsy did not reveal any abnormal cells or hemophagocytes. The repeat blood tests showed rising inflammatory markers. Her hemoglobin and platelet counts dropped further ( Figure 1).  , and antiscleroderma 70 were negative. C3 and C4 complement levels were normal. An ultrasound-guided kidney biopsy showed moderate effacement of foot processes with infrequent subepithelial immune type electrondense deposits consistent with membranous glomerulonephropathy (Figures 3-4). Phospholipase A2 receptor antibodies (PLA2R) were negative.

FIGURE 3: Electron microscopy of kidney biopsy showing subepithelial dense deposits FIGURE 4: Immunofluorescence microscopy view of the kidney showing dense deposits
Based on the clinical and laboratory criteria, she was diagnosed to have systemic lupus erythematosus (SLE) with type V lupus nephritis (membranous nephropathy).
The patient was treated with pulsed intravenous solumedrol and enalapril. Her fever subsided within 24 hours after starting steroids, and she was discharged with follow-up appointments with a rheumatologist, nephrologist, and ophthalmologist.

Discussion
SLE is a chronic inflammatory condition affecting multiple organs, and it affects females more than males.
The clinical course of the disease is variable and patients may not present with all the signs at the same time.
The clinical criteria are persistent fever, malar or discoid rash, photosensitivity, oral ulcers, serositis, psychosis, and chorea. Laboratory evidence includes hemolytic anemia, leukopenia, thrombocytopenia, false-positive venereal disease research laboratory (VDRL), renal involvement with proteinuria > 500 mg/24 hours (0.5 g/24 hrs), with positive serology (dsDNA, low C3 and C4, anti-Smith, anti-phospholipid antibodies). Proteinuria is the most common finding in lupus nephritis, which determines the long-term prognosis. Complications can result in end-stage renal disease with increased mortality.
HLH can be primary (autosomal recessive inheritance of gene mutation) or secondary to an infection, malignancy, and autoimmune diseases [4][5]. HLH secondary to rheumatological conditions or MAS has a prevalence of 0.9% to 4.5% [6]. The condition leads to loss of control of natural killer cells and cytotoxic lymphocytes over macrophages resulting in excessive immune activation and creating a cytokine storm destroying tissues [3][4][5]. It typically has a high d-dimer and a very high ferritin level, indicating the crucial role of macrophages in haem metabolism. Children who develop MAS secondary to a rheumatic disease can have high mortality rates from 5%-40% [6].
The 2019 European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) emphasized that positive ANA must be an entry criterion for the diagnosis of SLE, plus clinical criteria to have a weighted score of >10 [7]. Our patient had a weighed score of 20 using the following: fever (score 2), thrombocytopenia (score 4), anti-Smith antibody (score 6), class V lupus nephritis (score 8). The dsDNA was negative with a normal complement level, but anti-Smith antibodies and anti-sm/RNP antibodies were positive.

Conclusions
SLE is a multisystemic disease that is varied in its presentation and potentially a cause of pyrexia of unknown origin. There can be a significant clinical overlap between MAS secondary to SLE and COVID-19 infections with a cytokine storm (MIS-C). Patients with SLE nephritis may have normal complement levels and negative dsDNA. It is important to look for other antibodies like anti-sm/RNP antibodies and anti-smith antibodies. A renal biopsy will determine the final diagnosis.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.