A Case of Hemophagocytic Lymphohistiocytosis Secondary to Cytomegalovirus Infection

Final Diagnosis - Hemophagocytic lymphohistiocytosis secondary to cytomegalovirus infection in an immunocompetent individual.

History of the Present Illness

A 56-year-old woman initially presented in November 2020 with a 2-week history of almost daily subjective fever with chills.

She had daily fevers as high as 39.7 °C, along with nausea and emesis. Her initial work-up was extensive, but no source of infection was found. Extensive imaging studies were obtained, including transthoracic echocardiogram, CT scan of the head, and CT scan of the chest/abdomen/pelvis with contrast. All were unremarkable for source of infection, and no hepatosplenomegaly or lymphadenopathy was noted. The patient’s comprehensive metabolic panel demonstrated elevations in alanine aminotransferase and aspartate aminotransferase, as well as elevated Epstein-Barr virus and cytomegalovirus serum levels. However, her viremia was thought to represent reactivation caused by another acute illness and to not be primarily responsible for her fever, given her immunocompetence and unremarkable imaging. The patient was started on an empiric 2-week course of doxycycline.

A bone marrow biopsy revealed rare hemophagocytic cells, which raised the possibility that hemophagocytic lymphohistiocytosis (HLH) could be the source of her fevers. In addition to her bone marrow findings with hemophagocytosis, the patient met criteria for HLH with 4 other clinical findings: fever, hypertriglyceridemia, elevated ferritin, and an elevated soluble CD25 antigen (interleukin-2 receptor) result of 2818. She was started on a 7-week steroid taper for HLH, and she received 7 days of dexamethasone 15 mg daily. She discharged at the end of November 2020 after 18 days of hospitalization.

Unfortunately, the patient was readmitted in December 2020 for worsening lower extremity edema, dyspnea, and nausea. In the work-up for her new nausea, she received a diagnosis of Helicobacter pylori via stool antigen and was started on triple therapy. She was otherwise afebrile, and she was continued on her dexamethasone taper. A renal biopsy revealed collapsing focal segmental glomerulosclerosis, so diuresis was recommended to help with her lower extremity edema and dyspnea. Her creatinine improved over the course of this second hospitalization.

The patient appeared to be stable and improving until hospital day 9, when her fever reached 38 °C, which coincided with the tapering of her dexamethasone dose from 8 mg daily to 4 mg daily. She began to have daily fevers with temperature as high as 38.7 °C, as well as moderate diffuse abdominal pain. Additionally, the patient’s ferritin, triglycerides, CRP and ESR increased, causing concern for recrudescence of HLH. It was noted that her EBV viremia had resolved, but her CMV viral load was still elevated at 7750 IU/mL (down from 15,567 in November). On hospital day 18, an infectious disease specialist was consulted due to concern that the patient’s CMV viremia could be the primary trigger for her HLH.

Past Medical History

The patient presented with type 2 diabetes mellitus, hypertension, hyperlipidemia, and irritable bowel syndrome.

Key Medications

The patient was taking amlodipine, carvedilol, simvastatin, dicyclomine, and trimethobenzamide.

Epidemiological History

The patient has never smoked, drinks one glass of wine per week, and never used recreational drugs. She is sexually active and in a monogamous relationship with a man for the last 5 years, and lives with her children and pet cat. She works as a Certified Nursing Assistant. She briefly traveled to Miami one month prior to her initial admission, but denies any recent international travel.

Physical Examination

Upon examination her vitals included the following: Temperature: [98.7 °F (37.1 °C)-100.9 °F (38.3 °C)] 100.2 °F (37.9 °C); Pulse: [100-114] 100; blood pressure: (109-118)/(76-87) 118/84; and oxygen saturation was[96 %-98 %] 96 %. Exam was otherwise unremarkable.

Treatment and Follow-up

The infectious disease specialist ultimately recommended treating the patient’s CMV viremia due to concern for worsening HLH as the steroid dose was decreased. With her EBV viremia resolved, CMV was the only other potential HLH trigger that could be identified. Ganciclovir was renally dosed at 2.5 mg/kg daily. CMV levels were checked weekly with a plan to transition to a 3-month course of oral maintenance dosing once the patient had 3 consecutive CMV levels that were undetectable. By hospital day 29, repeat soluble CD25 returned at 1174 and the patient’s other laboratory values had improved, causing her to no longer meet criteria for HLH. Steroid taper also was completed. The patient’s CMV level became undetectable on hospital day 38.

Discussion

Human cytomegalovirus (or human herpesvirus 5) is a DNA virus from the Herpesviridae family. CMV is the largest and most complex herpesvirus, with a genome approximately 50% larger than that of HSV. CMV is commonly acquired during childhood and persists in epithelial cells in multiple organ types, and more notably CD34+ myeloid mononuclear stem cells within bone marrow.¹ The mechanism of CMV persistence is not well understood, but is generally attributed to an interplay of low-level chronic infection and a viral latency state brought on by viral gene self-regulation.² Prevalence studies suggest that more than 50% of the United States population is infected.

CMV infection typically results in mild disease in immunocompetent individuals, causing 10% to 20% of cases of heterophil-negative infectious mononucleosis in adults.¹ Patients who are pregnant or immunocompromised have more clinically significant CMV disease, which may lead to birth defects and opportunistic infections, respectively. However, within the last 20 years, there have been sporadic cases of HLH associated with CMV infection, suggesting that CMV may cause clinically significant disease beyond mononucleosis in immunocompetent individuals.

HLH is a rare but life-threatening multisystem syndrome resulting from a hyperactive immune system. It is thought to be caused by reduced negative feedback of macrophages, natural killer cells, and CD8+ lymphocytes, resulting in a hyperinflammatory state. HLH can be familial and associated with gene mutations, or it can be triggered by infection as with this patient. It is seen more frequently in children, but HLH affects individuals of all ages. It has an incidence of 1.2 cases per million individuals worldwide each year, but its presenting symptoms are nonspecific, thus underdiagnosis could be affecting its true incidence.

EBV is a major HLH trigger, but this patient’s EBV viremia had resolved by the time the patient began experiencing fevers during her second admission. CMV is an established trigger of HLH in immunocompetent children, but it is a rare trigger in immunocompetent adults. As of February 2020, there have been only 6 cases described in the literature of HLH secondary to cytomegalovirus infection in an immunocompetent adult.^3,4,5 We hypothesize that given CMV's proclivity to remain latent in CD34+ myeloid mononuclear stem cells, CMV could potentially have undiscovered downstream effects leading to HLH as monocytes differentiate into macrophages.

There are some aspects of this case that may prevent placing greater importance of CMV infection in immunocompetent individuals. Although CMV viremia levels were comparable across the case reports that are referenced, there was no effort to detect active CMV infection in lymph tissue. Another issue resulted from this patient’s ongoing gastritis, which could have increased her inflammatory makers and led to her meeting diagnostic criteria for HLH. Lastly, this patient was cotreated with both steroids and ganciclovir concurrently, and although steroids are a mainstay of treatment for both HLH, it is difficult to say definitively if the ganciclovir helped to resolve her HLH, or if she needed a longer steroid course. Further investigation may warrant case-control trials with intention-to-treat analysis regarding benefit of CMV treatment in immunocompetent patients with HLH.

Stephen Pagkalinawan, MD, completed his undergraduate and medical education at Rutgers, The State University of New Jersey, and his internal medicine-pediatrics residency at Maine Medical Center in Portland. He is working as a first-year adult infectious disease fellow at Temple University Hospital in Philadelphia, Pennsylvania, and also has an interest in LGBTQ+ health.

Have you worked on or know of a case study that you would consider having published, please feel free to contact Senior Editor John Parkinson at jparkinson@mjhlifesciences.com and I would be glad to have you discuss it with our medical editor.

References

1. ^{Bennett, JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Elsevier; 2020.}
2. ^{Beltran PMJ, Cristea IM. The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics. Expert Rev Proteomics. 2014;11(6):697-711. doi:10.1586/14789450.2014.971116}
3. ^{Atim-Oluk M. Cytomegalovirus associated haemophagocytic lymphohistiocytosis in the immunocompetent adult managed according to HLH-2004 diagnostic using clinical and serological means only. Eur J Microbiol Immunol (Bp). 2013;3(1):81-89. doi:10.1556/EuJMI.3.2013.1.12}
4. ^{Bonnecaze AK, Willeford WG, Lichstein P, Ohar J. Acute cytomegalovirus (CMV) infection associated with hemophagocytic lymphohistiocytosis (HLH) in an immunocompetent host meeting all eight HLH 2004 diagnostic criteria. Cureus. 2017;9(3):e1070. doi:10.7759/cureus.1070}
5. ^{Singh A, Chauhan A, Padole V, ChhabraD, Upneja R. The great masquerader: hemophagocytic lymphohistiocytosis secondary to cytomegalovirus infection in an immunocompetent young man. J Family Med Prim Care. 2020;9(7):3762-3765. doi:10.4103/jfmpc.jfmpc_274_20}