Reactivation of Parvovirus B19 Infection: An Uncommon Trigger of Macrophage Activation Syndrome in Adult-Onset Still’s Disease

A 40-year-old woman presented with four weeks of intermittent high-grade fever, cough, and joint pain, and two weeks of a generalized rash. She was found to have adult-onset Still’s disease (AOSD) and rapidly developed macrophage activation syndrome (MAS) on the second day of admission. Among infectious etiologies, Epstein-Barr virus and members of the herpes virus family are common triggers of MAS. However, our patient was found to have reactivation/recurrence of parvovirus B19 infection as the cause; this is an uncommon trigger reported infrequently in the medical literature. Despite intensive treatment, the patient passed away.


Introduction
Macrophage activation syndrome (MAS) is a form of hemophagocytic lymphocytic histiocytosis (HLH), which is a rare and life-threatening systemic inflammatory disorder that can occur in rheumatologic disorders. It is most commonly seen in systemic juvenile idiopathic arthritis (sJIA) in children but is often underrecognized in Kawasaki disease, systemic lupus erythematosus, and adult-onset Still's disease (AOSD) [1]. The mortality rate of MAS ranges between 20-42% [2]. This diagnosis is always challenging given the non-specific presentation and lack of definitive criteria, especially in adults in whom it is an uncommon syndrome. Due to the rapid progression and high mortality with MAS/HLH, clinical suspicion is the key to early diagnosis and treatment. We report a case of a patient with AOSD who had reactivation/recurrence of parvovirus B19 infection and then rapidly developed MAS with multiorgan failure.

Case Presentation
A 40-year-old woman with hypertension, transient ischemic attacks, and a history of squamous cell cancer of the tonsil in remission presented to the emergency department with complaints of four weeks of intermittent high-grade fever, dry cough, polyarticular and non-migratory joint pain involving knees, wrists, ankles, and elbows, and two weeks of a generalized rash on the trunk and lower extremities ( Figure 1). The rash usually came with a fever and went away when she was afebrile.   She was started on empiric vancomycin and cefepime. Her white blood cell count, platelet count, and liver enzymes three months prior to admission were normal. The next day, the patient's mentation deteriorated, and she required intubation. Magnetic resonance imaging of the head and electroencephalography were unremarkable. A lumbar puncture revealed lymphocytic pleocytosis (WBC 117/mm3, lymphocytes 78%) and a high CSF protein (100 mg/dL). CSF glucose and opening pressure were normal. All the cultures came back negative, and bacterial infection seemed less likely as the cause. Empiric acyclovir and doxycycline were added for possible herpes or spirochetes infection.
Despite fluid resuscitation, the patient developed worsening acute kidney injury and was started on renal replacement therapy. Hematologic malignancy/solid organ tumor was unlikely since flow cytometry obtained from blood was negative, and whole-body CT scans did not show any masses. Drug reaction with eosinophilia and systemic symptoms (DRESS) was a possibility, but the patient ingested only acetaminophen and ibuprofen for the past four weeks. Her rash was not typical for DRESS, a CBC did not show eosinophilia, and the skin biopsy was not consistent with DRESS. Vasculitis and autoimmune disorders were unlikely since the ANA and rheumatoid factor were negative, and the skin biopsy result did not have vasculitis features. So, MAS/HLH was likely since the patient met all four Yamaguchi major criteria for diagnosis of AOSD and three minor criteria ( Table 2).

Yamaguchi criteria for AOSD
The four major Yamaguchi criteria Fever of at least 39ºC (102.2ºF) lasting at least one week Arthralgias or arthritis lasting two weeks or longer A nonpruritic macular or maculopapular skin rash that is salmon-colored in appearance and usually found over the trunk or extremities  Additional laboratory tests ( Table 1) revealed elevated triglycerides (584 mg/dL), ferritin (>100,000 ng/mL), soluble interleukin-2 receptor (33950 pg/mL), and low fibrinogen (174 mg/dL); she met six out of eight criteria for HLH which included fever ≥38.5°C, splenomegaly, hypertriglyceridemia, hypofibrinogenemia, and elevated ferritin and soluble interleukin-2 receptor ( Table 3).      On repeat serology tests 10 days later, the parvovirus PCR was negative, but the parvovirus IgG remained positive consistent with reactivation/recurrence of parvovirus-B19 viremia, which is an uncommon event.

HLH-2004 diagnostic criteria
The patient was started on high-dose intravenous methylprednisone on the second day of admission due to high clinical suspicion of HLH/MAS even though multiple test results had not come back. Etoposide per HLH94 protocol was started on the fifth day of admission after the diagnosis of HLH/MAS was confirmed.
After the second dose of etoposide, the patient was more responsive. However, she developed severe pancytopenia, most likely a side effect of etoposide, and her hemodynamic status did not improve. Her family requested palliative care only, and she died one day after transitioning to comfort care.

Discussion
Adult-onset Still's disease is a rare systemic inflammatory disorder of unknown etiology characterized by spiking high fevers, arthritis or arthralgia, maculopapular salmon-colored rash, neutrophilic leukocytosis, and hyperferritinemia [4]. The Yamaguchi criteria is the most commonly used criteria for the diagnosis and have a sensitivity of 96.2% and specificity of 92.1% [5]. Macrophage activation syndrome/ hemophagocytic lymphocytic histiocytosis is the most serious and life-threatening complication of AOSD and is a dysregulated immune state possibly caused by abnormal downregulation of activated macrophages and lymphocytes leading to excessive cytokine production. It can occur as a primary/familial disorder or secondary disorder that is triggered by infection, malignancy, an autoimmune disease, or drugs. The diagnosis is based on the published diagnostic criteria used in the HLH-2004 trial which required at least five out of eight criteria ( Table 3) [6]. However, the HLH-2004 criteria were first developed for pediatric patients and may have some limitations in adult patients. Therefore, other classification/diagnostic tools have been developed. The HScore was developed to identify acquired HLH in adults, and a score of ≥ 250 indicated > 99% probabilities of HLH (a cut-off of 164 has a sensitivity of 100% and specificity of 89.9%) ( Table 4) [3]. The MS score ( Table 7) was developed to discriminate between MAS and active sJIA [7] and is under investigation for application in AOSD patients [8,9]. The calculated MS score for our patient was 10.807, and a score ≥ −2.1 indicates MAS with a sensitivity of 100% and specificity of 29.85% [10]. However, this score has not been validated in patients with AOSD. The frequency of AOSD patients who develop MAS can be as high as 10-15%, and patients may present with MAS at the time of diagnosis or during the disease course [11].
The MS score parameter β-coefficient 95% CI

TABLE 7: Best-fitted model with the best combination of clinical and laboratory variables and βcoefficients used for the calculation of the MS score
The etiology of MAS is unclear. However, infection, malignancy, genetic predisposition, medications, and flares of AOSD have been reported as potential triggers of MAS in AOSD [12]. The herpes virus family, including EBV, CMV, HSV, and varicella zoster, are the most common viral triggers [11]. Parvovirus-B19 has been reported as a less common trigger. However, our patient's serology results were consistent with the reactivation/recurrence of parvovirus-B19 infection as her trigger for MAS, which has been infrequently reported in the medical literature.
Parvoviruses are small, nonenveloped viruses with single-stranded DNA that has approximately 5000 nucleotides [13]. Transmission is predominantly by respiratory secretions but can occur through blood transfusion [14]. Adults typically present with arthralgias and possibly a macular rash. Unfortunately, due to the lack of controlled studies on the treatment, management is largely empiric. The treatment of MAS is different from that recommended for HLH. The mainstay of therapy is immediate highdose corticosteroids with methylprednisolone (1 g daily) for three to five consecutive days [11]. Cyclosporin (2-7 mg/kg daily) can be added in patients with an inadequate immediate response, as well as an IL-1blocking agent. In patients with severe active disease or CNS involvement, a reduced dose of etoposide (50-100 mg/m2 once weekly) can be very effective [18]. Studies with anakinra, cyclosporin, etoposide, plasma exchange, and immunoglobulin are conflicting. Investigation of malignancy should prompt malignancyspecific treatment [11]. In EBV-associated HLH, rituximab can be used as an additional treatment, and in HIV and malignancy-associated HLH, etoposide can sometimes be helpful. There are no studies on specific treatments for parvovirus B19-associated MAS.

Conclusions
Patients with HLH/MAS can rapidly decline. Early clinical suspicion is the key to prompt investigation and treatment. Thus, HLH/MAS should be one of the differential diagnoses in patients who present with sepsislike symptoms. High-dose intravenous corticosteroids should be started by the time of diagnosis without delay. Reactivation/recurrence of parvovirus-B19 infection can be one of the uncommon triggers of developing HLH/MAS.

Additional Information Disclosures
Human subjects: Consent was obtained or waived 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.