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Year : 2020  |  Volume : 9  |  Issue : 7  |  Page : 3762-3765  

The great masquerader: Hemophagocytic lymphohistiocytosis secondary to cytomegalovirus infection in an immunocompetent young man

Department of Medicine, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India

Date of Submission17-Feb-2020
Date of Decision13-Mar-2020
Date of Acceptance03-Apr-2020
Date of Web Publication30-Jul-2020

Correspondence Address:
Dr. Ajay Chauhan
Professor of Medicine, R. No 104, Academic Block, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, Ministry of Health and Family Welfare, Govt. of India, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jfmpc.jfmpc_274_20

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Hemophagocytic lymphohistiocytosis (HLH) is a rare, poorly recognized and underdiagnosed syndrome of excessive immune activation, which is rapidly fatal. HLH can occur as a familial or secondary disorder. Secondary HLH is most commonly associated with infections, malignancies, or autoimmune diseases. It primarily affects patients with a compromised immune system and rarely presents in immunocompetent individuals. Acute cytomegalovirus (CMV) associated HLH in the immunocompetent individual is extremely rare and only documented in five case reports till date. We, hereby, report a case of 18 years old young immunocompetent man who was diagnosed to have HLH secondary to CMV infection.

Keywords: Cytomegalovirus infection, hemophagocytic lymphohistiocytosis, immunocompetent

How to cite this article:
Singh A, Chauhan A, Padole V, Chhabra D, Upneja R. The great masquerader: Hemophagocytic lymphohistiocytosis secondary to cytomegalovirus infection in an immunocompetent young man. J Family Med Prim Care 2020;9:3762-5

How to cite this URL:
Singh A, Chauhan A, Padole V, Chhabra D, Upneja R. The great masquerader: Hemophagocytic lymphohistiocytosis secondary to cytomegalovirus infection in an immunocompetent young man. J Family Med Prim Care [serial online] 2020 [cited 2021 Jul 25];9:3762-5. Available from: https://www.jfmpc.com/text.asp?2020/9/7/3762/290781

  Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder with an incidence of 1.2 cases/million patients/year, with a shockingly high mortality rate.[1] HLH is characterized by defective natural killer cell cytotoxicity, which results in inappropriately robust activation of macrophages and leads to engulfment of other blood cells. This manifests as a syndrome of high fever, hepatosplenomegaly, lymphadenopathy, and cytopenias. HLH is frequently misdiagnosed for a septic syndrome, leading to a profound delay in diagnosis.[2] HLH is divided into primary and secondary. Secondary HLH results from insults such as infection, malignancies, or autoimmune diseases. Secondary HLH is characteristically caused by an exogenous insult in an immunocompromised patient. Common causes are Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), hepatitis A virus, herpes viridae, and bacterial, parasitic, and fungal etiologies.[3] CMV-associated HLH has been reported in a variety of immunocompromised states such as solid organ transplantation and autoimmune disease.[1] To our knowledge, CMV-associated HLH in an immunocompetent patient has been reported in the literature only on five other occasions.[1],[2],[4],[5],[6] We hereby report a case of a young immunocompetent man presenting with pancytopenia and eventually diagnosed to have HLH secondary to CMV infection.

  Case History Top

An 18-year-old young man presented with fever since 15 days and dry cough since 5 days. At presentation, the patient had pallor and hepatosplenomegaly on per abdomen examination. The patient's investigations showed hemoglobin of 9.5 gm%, total leucocyte count (TLC) of 1200/cumm (neutrophil-15%), and platelet count of 1.1 lac/cumm. Peripheral smear showed mild anisopoikilocytosis, mild hypochromia, normocytic to normochromic red blood cells and few microcytes. Patient's Serum Glutamic Oxaloacetic Transaminase (SGOT) and SGPT were elevated, i.e., 621 U/L and 246 U/L, respectively. Serum triglyceride levels were also elevated (273 gm/dl). The patient was evaluated on lines of pancytopenia. Malaria serology, rk 39, dengue serology, and scrub typhus serology were negative. Hbs antigen, anti-hepatitis C virus (HCV) and HIV were negative. Rheumatoid factor and antinuclear antibody were negative. Blood culture and urine cultures were sterile. During the stay in hospital, the patient also complained of diminution of vision. The fundus examination showed grossly defined hemorrhages. Bone marrow aspiration showed suppressed erythroid series, which was normoblastic in nature. Myeloid series showed normal maturation. Megakaryocytes were adequate. There was an increase in the number of macrophages that showed hemophagocytosis. There was no abnormal cell, granuloma, or parasite. The patient's serum ferritin was elevated (59013 ng/ml). Contrast-enhanced computed tomography (CECT) chest and abdomen showed hepatosplenomegaly with mild ascitis [Figure 1]. It also showed multiple centrilodular nodules with surrounding ground-glass opacities in bilateral lung fields and necrotic mediastinal lymphadenopathy [Figure 2]. The patient was diagnosed as HLH according to diagnostic guidelines for HLH -2004 [Table 1].[7]
Figure 1: CECT abdomen of patient showing hepatosplenomegaly

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Figure 2: CECT chest of patient showing multiple centrinodular nodules with surrounding ground glass opacities in bilateral lung fields

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Table 1: Revised diagnostic guidelines for HLH[7]

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The patient was treated with a broad spectrum antibiotic for febrile neutropenia. The patient was treated with Inj Etoposide and Inj dexa. Patient's CMV polymerase chain reaction (PCR) came out to be positive (1.1 *100 copies/ml) and he was started on antiviral (Inj gancyclovir). The patient was given blood transfusions. The patient did not respond and he subsequently developed type 1 respiratory failure because of the development of ARDS. Eventually, the patient succumbed to the disease and expired.

  Discussion Top

HLH represents a syndrome of cytokine dysregulation and severe inflammatory response. It is one of the only several diseases featuring a markedly elevated ferritin level in addition to adult-onset Still's disease and lymphoma. Also, many conditions can lead to the clinical picture of HLH, including malignancies, infections (viral, bacterial or parasitic), and rheumatoid disorders.

In primary HLH, 80% of these cases are present in the first year of life. Examples of genetic conditions associated with primary HLH include Griscelli syndrome 2 (GS2) and Chediak Higashi disease (CHD).[7] Secondary HLH arises due to an acquired precipitant. Both types have identical phenotypes characterized by inept NK cell/CD8+ T cell responses that lead to macrophage hyperactivation, proliferation, and infiltration into various organs.[1]

The typical findings of HLH are fever, hepatosplenomegaly, and cytopenia. Other common findings include hypertriglyceridemia, coagulopathy, and hypofibrinogenemia, elevated levels of ferritin, raised serum transaminase, and neurological symptoms. Histopathological findings include widespread accumulation of lymphocytes and mature macrophages, sometimes hemophagocytosis especially affecting the spleen, lymph nodes, bone marrow, and liver.[8]

H-score [Table 2] is used for determining the probability of having HLH.[9],[10] Our patient's H score was more than 250 which confers a 99% probability of HLH.
Table 2: Parameters included in H-Score and the number of points associated with each criterion for scoring[9],[10]

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HLH is an established phenomenon among immunosuppressed and children. Cases occurring in immunocompetent adults are few. Even more rare is CMV-associated HLH in an immunocompetent patient [Table 3].[2],[4],[5],[6]
Table 3: Prior cases of CMV-associated HLH infection in immunocompetent host

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HLH can be rapidly progressive and potentially fatal if left untreated. A major breakthrough was the use of epipodophyllotoxin derivative etoposide (150 mg/m2 per dose), in combination with steroids (IV/oral dexamethasone), which demonstrated induction of prolonged symptomatic resolution. The initial therapy covers the first 8 weeks of treatment [Figure 3]. There should be consideration of antiviral therapy in patients with ongoing viral infections, and intravenous immunoglobulin (IVIG) (0.5 g/kg IV) once every 4 weeks (during the initial and continuation therapy).
Figure 3: Induction therapy for treatment of HLH[7]IT MTX/HC=Intrathecal methotrexate and hydrocortisone

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Patients who can be weaned off of dexamethasone and etoposide without recurrence, recover normal immune function, and have no identified HLH-associated gene defects may stop therapy after the 8-week induction. Hematopoietic stem cell transplantation (HSCT) is generally recommended in patients with CNS involvement, recurrent/refractory disease, persistent NK cell dysfunction, or proven familial/genetic disease. [Figure 4] shows a schematic treatment overview of the HLH-2004 protocol.[7]
Figure 4: Schematic treatment overview of the HLH-2004 protocol.[7]VP-16-etoposide, I.T. therapy- intrathecal methotrexate and corticosteroids, HSCT- hematopoietic stem cell transplantation

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The mortality of secondary HLH and HLH in adults without treatment is high. Case series of adults treated with a variety of regimens report 30-day mortality of 20% to 44% and overall mortality of 50% to 75%.[8] Therefore, early diagnosis and treatment are crucial. Physicians at primary care level should be sensitized about HLH, as simple clinical examination and hemogram tests can facilitate in the timely diagnosis of HLH.

  Conclusions Top

HLH is a disorder that is usually present in immunocompromised patients but can be present in immunocompetent individuals too. It is a great masquerader of other conditions because of its variable presentation and this often leads to delayed diagnosis. Prompt commencement of immunochemotherapy is essential for survival. Therapy is complicated by high risk of treatment-related morbidity and disease recurrence.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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;3:81-9.  Back to cited text no. 1
Tseng YT, Sheng WH, Lin BH, Lin CW, Wang JT, Chen YC, et al. Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults. J Microbiol Immunol Infect 2011;44:191-7.  Back to cited text no. 2
Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol 2013;161:609-22.  Back to cited text no. 3
Hot A, Madoux MH, Viard JP, Coppéré B, Ninet J. Successful treatment of cytomegalovirus-associated hemophagocytic syndrome by intravenous immunoglobulins. Am J Hematol 2008;83:159-62.  Back to cited text no. 4
Tsuda H, Shirono K. Successful treatment of virus-associated haemophagocytic syndrome in adults by cyclosporin A supported by granulocyte colony-stimulating factor. Br J Haematol 1996;93:572-5.  Back to cited text no. 5
Bonnecaze KA, Willeford GW, 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:e1070.  Back to cited text no. 6
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.  Back to cited text no. 7
Schram MA, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood 2015;125:2908-14.  Back to cited text no. 8
Debaugnies F, Mahadeb B, Ferster A, Meuleman N, Demulder ARL, Corazza F. Performances of the H-Score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients. Am J Clin Pathol 2016;145:862-70.  Back to cited text no. 9
Mbachi C, Igwilo R, Flores E, Chukwujindu E, Mba B. A rare case of hemophagocytic lymphohistiocytosis in an adult with diffuse large B-cell lymphoma. Case Rep Hematol 2019;2019:1-3.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3]


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