Secondary hemophagocytic lymphohistiocytosis due to Heartland virus

Background

Heartland virus (HRTV), a virus of the Phlebovirus genus of the Bunyaviridae family, was discovered in 2009 in Missouri, USA, after two men fell ill with fever, diarrhoea, fatigue, thrombocytopenia, and leukopenia.1 In 2013, the Centers for Disease Control and Prevention implemented a national protocol to define the geographic distribution, epidemiology and clinical characteristics of HRTV and to develop diagnostic assays.2 Based on this protocol (2013 to 2017), 16 patients with acute HRTV were identified. All patients were men with mean age of 71 (range: 43–80 years). Disease onset occurred between April and September, with the majority (50%) occurring in June. All patients had fever, thrombocytopenia and leukopenia (part of enrollment criteria) with the majority of patients endorsing fatigue, anorexia, nausea, headache, confusion, arthralgia, myalgia and diarrhoea.2 Fourteen (88%) of the patients were hospitalized, with two not surviving the hospitalization.2 Since discovery of HRTV in 2009, more than 50 cases of HRTV have been reported, primarily concentrated in the Midwestern USA.3 In the medical literature, there has been one prior case of secondary hemophagocytic lymphohistiocytosis (HLH) due to HRTV in an immunocompromised host.4

The Lone Star tick (Amblyomma americanum) has been identified as the vector for HRTV.2 Amblyomma americanum is the vector for multiple tickborne pathogens, including Ehrlichia chaffeensis, E. weingii, Franciscella tularensis and HRTV.5 In the USA, the incidence of tickborne illness is increasing, as ticks expand their geographic range.5 While Amblyomma americanum has historically been geographically located in the Midwest, it has now extended into the Southeastern and Northwestern USA and Canada. This expansion is thought to be due to warmer temperatures associated with climate change.5

Case presentation

A man in his 90s from the mid-Southeastern USA with a history of Crohn’s disease not on immunosuppressive therapy, type II diabetes mellitus, chronic kidney disease stage III, a prior cardiovascular accident with no residual deficits, and hypertension presented with acute onset of fever, fatigue, myalgias and non-bloody diarrhoea. The patient lived in a heavy wooded area, and a tick was reportedly removed from his left forearm three weeks prior to presentation. On presentation, vitals were notable for temperature 101.8°F, blood pressure 154/58 mmHg, heart rate 83 beats per minute, and Sp02 95% on room air. He was ill-appearing on examination, with abdominal distention and non-specific abdominal tenderness. No skin manifestations were present. Laboratory analysis on presentation is shown in table 1. Cell lines and hepatic transaminases were normal five months prior.

A Lone Star tick (figure 1) was found embedded on the patient. He was initiated on empiric treatment for tick-borne illness on day 3 of hospitalization. Despite appropriate treatment, the patient clinically worsened with fever, worsening mental status and lactic acidosis, prompting intensive care unit (ICU) admission on hospital day 6. A lumbar puncture was attempted due to concern for possible meningitis or encephalitis but was unsuccessful and further attempts were declined by family due to goals of care. Given inability to obtain cerebral spinal fluid studies, he was empirically treated for meningoencephalitis with a 7-day course of intravenous ampicillin and ceftriaxone and 14 days of intravenous acyclovir.

Imaging of the brain (CT brain stroke protocol, MRI brain with and without contrast) was unrevealing. CT abdomen and pelvis with contrast showed non-specific mesenteric stranding along with the inferior mesenteric vessels, although not associated with any bowel wall thickening or pericolonic inflammation. An abdominal ultrasound reported coarsened echotexture with nodular contour and splenomegaly. A CT abdomen and pelvis 2 years prior to admission reported normal liver appearance and spleen.

Based on clinical presentation and evolving laboratory analysis, the patient was diagnosed with secondary HLH on day 10 of hospitalization, as he met five of eight criteria for HLH, with fever, splenomegaly, cytopenias affecting at least two of three lineages in the peripheral blood, hypertriglyceridemia/hypofibrinogenemia and ferritin elevation ≥500 μg/L, based on the 2004 revised guidelines for diagnosis of HLH.6 He also had a H-score of 268, indicating a >99% probability of HLH.7 A bone marrow biopsy to confirm hemophagocytosis was not obtained, as it was outside family’s goals of care, and soluble CD25 level and natural-kill cell activity, two other diagnostic criteria, are unknown. Given association of HLH with autoimmune, oncologic and infectious aetiologies,6 a broad evaluation was completed (table 2), including a HRTV reverse transcriptase-PCR (RT-PCR) sent on hospital day 6 due to no response to doxycycline.

Rheumatology recommended treatment with steroids and anakinra for secondary HLH. He was initiated on high-dose steriods on hospital day 7 and anakinra (starting hospital day 10 through 20). The patient’s clinical status (fever, mental status, cytopenias, and transaminase elevation) improved over the week following initiation of HLH therapy, allowing transfer out of the ICU on hospital day 15. Due to his age, complex needs, and goals of care, he was discharged home with home hospice services. After discharge, the primary medical team was contacted by the local health department due to a positive HRTV RT-PCR result.

Differential diagnosis

Based on tick exposure history, clinical presentation and laboratory abnormalities of leukopenia, thrombocytopenia, and hepatic transaminase elevation, suspicion was high for tickborne illness. As a Lone Star tick was removed from the patient’s body, differential diagnosis included infections transmitted by Amblyomma americanum, including ehrlichiosis, tularemia and HRTV.5 He was empirically treated with doxycycline, though clinically worsened.

Per the 2004 revised diagnostic guidelines for diagnosis of HLH, a diagnosis of HLH can be made if one of the following criteria are met: a molecular diagnosis consistent with HLH or at least five of eight diagnostic criteria for HLH are fulfilled.6 The patient in this report was diagnosed with secondary HLH, as he met five of eight diagnostic criteria. Furthermore, the patient’s H-score, a diagnostic score for HLH validated in an adult cohort, was 268, indicated a >99% probability of HLH.7 8

Given secondary diagnosis of HLH and lack of response to doxycycline, a broad infectious, autoimmune and oncologic work up was completed (table 2).6 Due to otherwise negative autoimmune, malignant and infectious work up, when laboratory analysis returned with positive HRTV PCR, the patient was diagnosed with secondary HLH due to HRTV. While the patient did have a positive E. Chaffeensis IgG with titre 1:512 (negative IgM), DNA RT-PCR was negative and repeat serologic testing was negative (IgM, IgG). The positive E. Chaffeensis IgG likely represents prior infection, as the patient and family reported multiple tick exposures, or a false positive in setting of his systemic inflammatory state, rather than active infection. This was important to elucidate, as there have been case reports of secondary HLH due to E. Chaffeensis.9–15

Treatment

The patient was empirically treated with doxycycline for presumed tickborne illness though continued to worsen clinically. After diagnosis of HLH, he was treated with steriods (starting day 7; dexamethasone 20 mg×8 days, followed by dexamethasone taper of 10 mg×1 day, 8 mg×1 day, 6 mg×2 days and discharged with prednisone taper of 20 mg×1 week, 15 mg×1 week, then 10 mg until follow-up) and anakinra (starting day 10 through 20, 100 mg four times per day×2 days, then 100 mg two times per day). Historically, based on the HLH 2004 treatment guidelines, initial therapy for HLH includes etoposide, dexamethasone, and cyclosporine.6 However, this regimen is associated with significant morbidity and mortality, with adverse effects including secondary infections, myelotoxicity, hepatic dysfunction, and secondary malignancies.16 To avoid the potentially toxic effects of these medications, anticytokine therapy with anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, with and without glucocorticoids, has been used to treat both primary and secondary HLH,16 as genes associated with pro-inflammatory cytokines, such as IL-1, have been shown to be elevated in HLH.17 Anakinra has been used to successfully treat secondary HLH due to cytomegalovirus18 and macrophage activation syndrome,19–25 a subcategory of HLH. Treatment with anakinra is a feasible treatment option for patients with secondary HLH.16 This case report provides evidence that anakinra with high-dose steriods may be an effective treatment option for secondary HLH due to HRTV infection.

RT-PCR for HRTV returned positive after the patient was discharged home. There are currently no vaccines to prevent or medications to treat HRTV infection.26 As the virus is transmitted through tick bites, insect repellants, clothing barriers, avoidance of heavily wooded areas, and tick checks after possible exposure can prevent disease transmission.

HRTV infection should be considered when a patient presents with fever, leukopenia and thrombocytopenia, and does not respond to empiric therapy for other tickborne illness, such as Ehrlichia and Anaplasma.2 26 Increased clinician awareness of HRTV is needed, given the geographic expansion of the Lone Star tick in the setting of climate change.5 Treatment of HRTV infection is supportive care.3 Analgesics and antipyretics can be used to reduce pain and fever. In severe cases, intravenous fluids, ventilator support, vasopressors, blood products, or dialysis may be required.2

Outcome and follow-up

The patient was initiated on HLH therapy and had clinical response leading to transfer out of the ICU on hospital day 15. Despite improvement in his clinical presentation including mental status, the patient elected to be discharged home with home hospice services due to his age, debility, and goals of care. Three weeks after hospital discharge, the patient graduated from hospice services due to improvement in mobility and mental status. He is following with rheumatology in the outpatient setting with plan for continued prednisone taper. At 3-month post-hospital follow-up, his pancytopenia had resolved, serum creatinine was at baseline, and hepatic transaminases and ferritin were within normal range (table 1).