Concomitant Hemophagocytic Lymphohistiocytosis and Cytomegalovirus Disease: A Case Based Systemic Review

Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) is an immune mediated life-threatening condition. It is driven by an overactivation of the immune system and causes inflammatory tissue damage potentially leading to organ failure and death. Primary HLH is caused by genetic mutations, while secondary HLH is triggered by external factors. Viral infections are a well-known cause of secondary HLH. Cytomegalovirus (CMV) is a virus in the herpes family known to cause HLH in rare cases.

Methods: We report a recent case of CMV-induced HLH, followed by a systematic review of described cases of this rare disease entity, through a structured search in the medical database PubMed. All articles were assessed on a predetermined set of inclusion criteria.

Results: A total of 74 patients (age > 18 years) with CMV-related HLH were identified, 29 men, 42 women, and three patients with unspecified gender. Median age was 37.5 years (range 18-80). Sixty-six patients (88%) had one or more comorbid conditions and 22 patients (30%) had inflammatory bowel disease (IBD), the most frequent comorbidity. Forty patients (54%) received some form of immunomodulating treatment prior to HLH development. The general treatment approach was in general dual, consisting of antiviral treatment and specific immunomodulating HLH treatment approaches. Treatment outcome was at 77% survival, while 23% had fatal outcome.

Conclusion: The findings highlight the importance of early diagnostic work up and treatment intervention. Ability to recognize the characteristic clinical traits and perform specific HLH diagnostic workup are key factors to ensure targeted diagnostic work and treatment intervention for this patient group.

Keywords: HLH; cytokines; cytomegalovirus (CMV); immunosuppression; inflammatory bowel diseases (IBD).

Figure 1

Clinical and laboratory evaluation during hospitalization. (A) A timeline of diagnostic and therapeutic events over the course of admission. (B) Plasma CMV-DNA PCR transcript levels over the course of treatment. (C) Hemoglobin (Hb) and white blood cell count (WBC) during hospitalization. (D) Platelets and lactate dehydrogenase (LDH) during hospitalization. (E) Ferritin and C-reactive protein (CRP) during hospitalization.

Figure 2

Bone marrow biopsy and CT examination. Bone marrow biopsy from the patient demonstrating; (A) modest hypocellularity; (B) higher magnification demonstrating granuloma formation with inflammation; (C) macrophages with marked hemophagocytosis; (D) giant cells. (E) CT abdomen showing hepatosplenomegaly with “kissing sign”.

Figure 3

Flow chart of literature search process. The search and elimination process illustrated by a flow chart. The search led to 64 articles describing patient cases of CMV-associated HLH. Six of the articles described more than one relevant patient case. In total, 73 patient cases were included from literature.

Figure 4

Distribution of age, gender, and cytopenias. (A) Illustrates distribution of age and gender. Patients of unknown age/gender are not included. (B) Illustrates the distribution of degrees of cytopenia.