A Rare Case of CMV-induced HLH in B-ALL

Krishna Chaitanya K https://orcid.org/0000-0002-5367-9024

Department of Critical Care, Care Hospital, Hyderabad, Telangana, India

Corresponding Author: Krishna Chaitanya K, Department of Critical Care, Care Hospital, Hyderabad, Telangana, India, Phone: +91 6300583870, e-mail: appuniq@gmail.com

Received: 24 August 2023; Accepted: 19 October 2023; Published on: 02 January 2024

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a condition that demands a high index of suspicion and necessitates differentiation from sepsis as the treatment approaches for these two conditions diverge. Patients afflicted with hematological malignancies are susceptible to developing secondary HLH syndrome, which can arise either due to the malignancy itself or due to infections that emerge during chemotherapy. Prudent administration of chemotherapy regimens and the early identification of secondary HLH, whether attributed to malignancy or to infections, are pivotal in tailoring appropriate treatments and thereby mitigating mortality. This case involves a 50-year-old male diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) and undergoing induction chemotherapy. The patient exhibited refractory shock without discernible sources of infection on routine cultures, along with normal procalcitonin levels. Additionally, acute liver failure and pancytopenia developed. Through diagnostic investigations, hemophagocytes were identified in bone marrow biopsy, and cytomegalovirus (CMV) viral load was detected in the blood, satisfying the Histiocyte Society’s criteria for HLH. HLH often mimics sepsis, even though it can itself be triggered by an infection. Hence, it is imperative to accurately identify, differentiate, and treat both conditions appropriately.

How to cite this article: Chaitanya K K. A Rare Case of CMV-induced HLH in B-ALL. Indian J Crit Care Case Rep 2024;3(1):14–17.

Source of support: Nil

Conflict of interest: None

Keywords: Case report, Hemophagocytic lymphohistiocytosis, Septic shock, Steroid

INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a condition that demands a high index of suspicion and necessitates differentiation from sepsis as the treatment approaches for these two conditions diverge. Patients afflicted with hematological malignancies are susceptible to developing secondary HLH syndrome, which can arise either due to the malignancy itself or due to infections that emerge during chemotherapy. Prudent administration of chemotherapy regimens and the early identification of secondary HLH, whether attributable to the malignancy or to infections, are pivotal in tailoring appropriate treatments and thereby mitigating mortality. This case involves a 50-year-old male diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) and undergoing induction chemotherapy. The patient exhibited refractory shock without discernible sources of infection on routine cultures, along with normal procalcitonin levels. Additionally, acute liver failure and pancytopenia developed. Through diagnostic investigations, hemophagocytes were identified in bone marrow biopsy, and cytomegalovirus (CMV) viral load was detected in the blood, satisfying the Histiocyte Society’s criteria for HLH. HLH often mimics sepsis, even though it can itself be triggered by an infection. Hence, it is imperative to accurately identify, differentiate, and treat both conditions appropriately.¹

CASE DESCRIPTION

A 50-year-old male was admitted to the intensive care unit with complaints of generalized weakness, fever with chills for the past 2 days, vomiting, and abdominal distension without passage of stools for 2 days (There was no history of any addiction). He was undergoing induction chemotherapy for Philadelphia chromosome-negative (B-ALL), consisting of 4 weeks of prednisolone, four doses of vincristine, three doses of daunorubicin, and two doses of l-asparaginase. Upon arrival, he presented in shock with hyperlactemia that required vasopressor support following fluid resuscitation. Empirical antibiotics (meropenem and linezolid) were initiated after sending blood and urine cultures. On examination, he was conscious and responsive to commands, with no added lung or cardiac sounds on auscultation. Abdominal distension was observed without tenderness. His chest X-ray and two-dimensional echocardiogram were normal. An initial abdominal ultrasound indicated hepatomegaly with mild heterogeneous echotexture of the liver. Laboratory parameters revealed pancytopenia (hemoglobin: 7.8 gm/dL, white blood cell count: 1,700, platelet count: 60,000), hyponatremia, hypophosphatemia, and elevated bilirubin [5 mg/dL, serum glutamic oxaloacetic transaminase (SGOT): 59, serum glutamic pyruvic transaminase (SGPT): 119, alkaline phosphatase: 290]. Amylase, lipase, blood urea, creatinine, and thyroid-stimulating hormone were within normal ranges. Procalcitonin levels were normal. Workup for viral hepatitis [immunoglobulin M (IgM)—hepatitis A virus, IgM-hepatitis B (HB) core antigen (Ag), HB surface Ag, anti-hepatitis C virus, and IgM-hepatitis E virus], HIV, and tropical fever were negative. Cultures (blood and urine) showed no growth. Certain abnormalities in liver test results are common in patients treated with asparaginase or pegaspargase, often including decreased serum albumin and clotting factors (II, V, VII, VIII, IX, prothrombin, and fibrinogen), elevated alkaline phosphatase, and occasionally increased serum aminotransferase levels and bilirubin. Our patient had normal prothrombin levels, predominant hyperbilirubinemia, and normal serum albumin levels.²^,³

A contrast-enhanced computed tomography (CECT) abdomen revealed an enlarged liver (169 mm) with diffuse hypoattenuation of parenchyma, a normal intrahepatic bile duct (IHBD) portal radicle, diffuse dilatation of jejunal and ileal loops with no distinct transition point, minimal ascites, and mild mesenteric fat stranding in the right iliac fossa (Fig. 1). Due to persistent cytopenia despite platelet transfusions, filgrastim injection was administered. An empirical antifungal was introduced due to ongoing fever spikes, deteriorating shock, and worsening liver function tests (Fig. 2) (bilirubin 10, direct 5.9, SGOT 103, SGPT 112, INR 1.6). Given ongoing pancytopenia, a bone marrow biopsy was performed, revealing hemophagocytes in a hypercellular bone marrow without any blasts. Intubation was deemed necessary due to poor Glasgow Coma Scale, hyperammonemia, and refractory shock. The diagnosis of HLH was established based on the Histiocyte Society’s criteria, with more than five out of eight criteria fulfilled (fever, cytopenia in more than two lineages, high ferritin of 6865 mg/dL, hemophagocytes in bone marrow, and other supportive criteria of transaminase elevation, hyperbilirubinemia, and hyponatremia). Dexamethasone 8 mg twice daily was initiated. An etiological workup using an angiotensin-converting enzyme (ACE) panel [adenovirus, CMV, Epstein–Barr virus (EBV)] detected a CMV viral load of 5811.83 IU/mL (Fig. 3). Despite initiating ganciclovir, the patient’s clinical condition deteriorated, and he could not be saved due to worsening shock, deteriorating liver function, and acute liver failure.⁴^,⁵

Fig. 1: A CECT of the abdomen revealed an enlarged liver (169 mm) with diffuse hypoattenuation of parenchyma, a normal IHBD portal radicle, diffuse dilatation of jejunal and ileal loops with no distinct transition point, minimal ascites, and mild mesenteric fat stranding in the right iliac fossa

Fig. 2: Progressive worsening of serum bilirubin levels

Fig. 3: Etiological workup using an ACE panel (adenovirus, CMV, and EBV) detected a CMV viral load of 5811.83 IU/mL

DISCUSSION

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder marked by the dysregulation of immune responses, leading to excessive activation of immune cells and subsequent cytokine storm. HLH can manifest as primary, arising from genetic aberrations affecting immune cell function, or secondary, resulting from underlying conditions such as infections, autoimmune disorders, or hematological malignancies. The prevalence of HLH is estimated at 1 in 50,000 to 1 in 200,000 births, with a predilection for pediatric cases.

Diagnostic Criteria

The HLH diagnostic criteria, initially established in 1991 and revised in 2004, serve as a pivotal guideline for identifying individuals with this complex syndrome. Herein, we outline the classic HLH-2004 criteria and subsequent modifications that have enhanced diagnostic accuracy.

Modifications and Refinements

In subsequent years, efforts have been made to refine the diagnostic criteria and increase sensitivity while maintaining specificity. Notable modifications include HLH 2009 modified criteria shown in Table 1.

**Table 1:** Hemophagocytic lymphohistiocytosis (HLH) diagnostic criteria, 2009
Molecular diagnosis of HLH or X-linked lymphoproliferative syndrome (XLP)
At least three of four: Fever. Splenomegaly. Cytopenias (minimum two cell lines reduced). Hepatitis.
At least one of four: Hemophagocytosis. ↑Ferritin. ↑Interleukin-2 receptor subunit-α (age-based). Absent or very decreased NK function.
Other results supportive of HLH diagnosis: Hypertriglyceridemia. Hypofibrinogenemia. Hyponatremia.

The patient met four of the criteria (fever, cytopenia, hepatitis, cytopenia) and two of the four criteria of hemophagocytosis positive, hyperferritinemia, along with other supportive criteria.

Genetic testing: Recognizing primary HLH’s genetic basis, genetic testing for known mutations (PRF1, UNC13D, STX11, STXBP2, SH2D1A, XIAP) has been integrated into diagnostic protocols.

Hemophagocytic lymphohistiocytosis (HLH) 2004/2009 hybrid criteria: These criteria combine the original HLH 2004 criteria with the inclusion of genetic testing, enhancing diagnostic accuracy in genetically predisposed cases.

HScore: An algorithmic approach that utilizes clinical and laboratory parameters, the HScore aids in distinguishing HLH from other hyperinflammatory conditions.

Treatment

Hemophagocytic lymphohistiocytosis (HLH) necessitates a comprehensive therapeutic strategy to counteract immune dysregulation and mitigate potential organ damage. Both historical and contemporary treatment regimens are essential for managing this complex syndrome. This article provides an overview of the established and novel HLH treatment protocols, including drug dosages.

Various treatment modalities used are as per Figure 4.

Fig. 4: Various treatment modalities used for HLH

Traditional treatment regimens for HLH are included in Table 2.

**Table 2:** Traditional treatment regimens
Drug	Dose	Role
High-dose corticosteroids (dexamethasone)	Typically initiated at 10 mg/m²/day (or equivalent), divided into multiple doses	Suppression of inflammation and immune hyperactivity
Etoposide	Often administered at 150–300 mg/m² over 3–5 days	Targeting rapidly dividing immune cells, including activated macrophages
Cyclosporine or tacrolimus	Cyclosporine dosed at 3–10 mg/kg/day or tacrolimus dosed at 0.1–0.15 mg/kg/day	Modulation of T-cell responses and cytokine production
Emapalumab (anti-interferon-γ antibody)	Initiated at 1 mg/kg intravenously, followed by 0.5 mg/kg weekly	Targeting interferon-γ to temper immune activation
Ruxolitinib (Janus kinase inhibitor)	Initiated at 5 mg orally twice daily	Inhibition of intracellular signaling pathways to reduce cytokine storm
Hematopoietic stem cell transplantation	Patient-specific conditioning regimens followed by stem cell infusion	Curative intervention for primary HLH cases, restoring healthy immune function
Individualized immunomodulation	Doses are tailored based on the patient’s clinical response and immune profile	Curative intervention for primary HLH cases, restoring healthy immune function

CONCLUSION

Hemophagocytic lymphohistiocytosis (HLH), though rare, represents a formidable clinical challenge requiring timely recognition and expert management. This review underscores the intricate facets of HLH, encompassing its diverse presentation, diagnostic intricacies, multifaceted treatment regimens, and its interplay with hematological malignancies. A holistic approach, harmonizing immunomodulation with trigger eradication, is indispensable in enhancing the prognosis of HLH patients.

ORCID

Krishna Chaitanya K https://orcid.org/0000-0002-5367-9024

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