Hemophagocytic lymphohistiocytosis (HLH) is a rare heterogeneous group of disorders characterized by immune overactivation. It can occur because of primary genetic mutations or secondary to almost any inflammatory or infectious process. The clinical manifestations of this syndrome are varied and life-threatening and resemble those of many malignancies, infections, sepsis, and multisystem inflammatory syndrome in children. Laboratory abnormalities often are not diagnostic for HLH until late in the disease course, and the laboratory studies are send-out tests at most institutions. Thus, quickly and accurately diagnosing pediatric patients with HLH presents significant challenges to the clinician. Furthermore, there has been recent discussion in the literature regarding the use of diagnostic criteria for HLH. In this case report, we detail an adolescent male individual who developed persistent unexplained fever, rhabdomyolysis, and regional ischemic immune myopathy. To our knowledge, there is no previous report of a pediatric patient with this rare myopathy or HLH presenting with persistent rhabdomyolysis in the literature. The patient was hospitalized for a total of 61 days, with multiple treatments attempted throughout during his course of illness. In this report, we highlight the importance of using diagnostic flexibility when HLH is suspected in pediatric patients and provide insight into the unique challenges of identifying this condition.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome characterized by immune hyperactivation, including unremitting fever, cytopenias, hepatosplenomegaly, coagulopathy, and elevation in biomarkers, including ferritin and soluble interleukin 2 receptors (sIL-2).13  HLH can be caused by primary genetic factors or secondary reactive factors. Secondary HLH is commonly referred to as macrophage activation syndrome (MAS) or reactive HLH. Diagnosis is challenging because HLH often arises as sequelae of another acute or chronic disease process, such as underlying malignancy, rheumatic disease, viral infection, or juvenile idiopathic arthritis.4,5  Thus, identifying the underlying cause of primary or secondary HLH is crucial in treating the syndrome. In this report, we describe a case of HLH-like syndrome in a previously well adolescent who presented with fever of unknown origin, myositis, and rhabdomyolysis resulting in a hospital stay totaling >2 months.

A 15-year-old previously healthy male individual presented to his pediatrician with complaints of fever, fatigue, and bilateral thigh pain for the past week. He reported no recent illnesses and denied any activity or injury that could be responsible for the thigh pain. His examination was reassuring, and a coronavirus disease 2019 (COVID-19) test was negative. Over the next week, the patient continued to experience night sweats, fatigue, bilateral quadriceps pain, and fevers to 38.9°C. He had multiple telephone and in-person visits with his pediatrician as well as laboratory workup. This was notable for aspartate transaminase (AST) of 307 U/L (normal: <36 U/L), alanine aminotransferase (ALT) of 148 U/L (normal: <60 U/L), creatinine kinase (CK) of 10 887 U/L (normal: 0 to 253 U/L), C-reactive protein (CRP), and urinalysis. Infectious disease and nephrology specialists recommended further viral and laboratory workup as well as aggressive hydration. On day 13, the patient presented to the pediatrician once again. His physical examination revealed a tired but well-appearing teenager boy in no apparent distress. He denied dark-colored urine, dysuria, melena, clay-colored stools, skin findings, or upper respiratory symptoms, and his temperature was 37.8°C. Laboratory evaluation revealed serum creatinine of 0.86 mg/dL (normal: 0.46 to 0.81 mg/dL), AST 447, ALT 289, lactate dehydrogenase (LDH) 1229 U/L (normal: 105 to 235 U/L), CK 13 226, and leukocytosis 1.78 with 35% bands. Epstein-Barr virus panel, HIV, and repeat COVID-19, erythrocyte sedimentation rate (ESR), and CRP tests were all negative. Chest radiograph and electrocardiogram were unremarkable. The next day, the patient was admitted to the hospital for continued fevers to 39°C and increasing CK with concern for rhabdomyolysis.

On admission, the patient continued to complain of fatigue, fever, and bilateral thigh pain. Physical examination was notable for pain with palpation of both quadriceps. He had no rashes or other skin findings. Laboratory tests at time of admission revealed persistently elevated CK, LDH, and transaminases (Table 1). Over the next week, these laboratory markers continued to increase and the patient remained febrile to 39.5°C. An extensive workup was performed in consultation with multiple pediatric subspecialists in search of a unifying diagnosis for his continued rhabdomyolysis and fever. An electrocardiogram and hematopathology blood smear performed at this time were unremarkable, making Kawasaki disease, endocarditis, and primary hematologic or oncologic process less likely. Juvenile idiopathic arthritis was deemed unlikely because of the absence of arthritis or quotidian fever pattern. The patient’s continually negative antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies, normal ESR, CRP, complement levels, and cryoglobulin levels were not supportive of a rheumatologic cause of his symptoms, such as polymyositis. Diagnostic testing, including HIV, cytomegalovirus, Epstein-Barr virus, COVID-19 immunoglobulin G, herpes simplex virus, varicella zoster virus, influenza A and B, Bartonella, Bordatella, chlamydia, cryptospirosis, gonorrhea, quantiferon tuberculosis, gamma-glutamyl transferase, ANA, blood cultures ×3, antistreptolysin O, rapid plasma reagin, CRP, ESR, thyroid function, complement levels, methylmalonic acidemia, B12, acyl-carnitine, and cardiolipin antibody tests all returned within normal limits. Elevations in mycoplasma immunoglobulin M and immunoglobulin G were found, for which the patient was treated with a 10-day course of doxycycline with no improvement.

TABLE 1

Laboratory Values Throughout Disease Course

AdmissionHospital Day 5Hospital Day 11Hospital Day 38Hospital Day 59
WBC: (normal 4.9–15.5 K/mm31.39 1.27 2.43 <0.10 2.06 
Hemoglobin: (normal 13–16 g/dL) 12.3 10.9 9.9 8.0 11.0 
AST (normal: <36 U/L) 482 836 973 242 229 
ALT (normal: <60 U/L) 310 648 503 175 149 
LDH (normal: <285 U/L) 1307 1735 1970   
CK (normal: 0–253 U/L) 12 638 15 224 33 983 6082 3265 
Ferritin (normal: 20–155 ng/mL) 2005 3412 5232 14 825 16 239 
sIL-2 (normal: 137–838 U/L) — 2249 — 3774 2244 
Perforin (normal: 98–181 MCF) — 249 — — — 
Granzyme B (normal: 152–825 MCF) — 1134 — — — 
CD107a (normal: 207–678 MCF) — 964 — — — 
Triglycerides (normal: <150 mg/dL) — — 194 222 381 
CXCL9 (normal: <12 pg/mL) — — — 122 037 — 
Il-18 (normal: 89–540 pg/mL) — — — 8350 — 
AdmissionHospital Day 5Hospital Day 11Hospital Day 38Hospital Day 59
WBC: (normal 4.9–15.5 K/mm31.39 1.27 2.43 <0.10 2.06 
Hemoglobin: (normal 13–16 g/dL) 12.3 10.9 9.9 8.0 11.0 
AST (normal: <36 U/L) 482 836 973 242 229 
ALT (normal: <60 U/L) 310 648 503 175 149 
LDH (normal: <285 U/L) 1307 1735 1970   
CK (normal: 0–253 U/L) 12 638 15 224 33 983 6082 3265 
Ferritin (normal: 20–155 ng/mL) 2005 3412 5232 14 825 16 239 
sIL-2 (normal: 137–838 U/L) — 2249 — 3774 2244 
Perforin (normal: 98–181 MCF) — 249 — — — 
Granzyme B (normal: 152–825 MCF) — 1134 — — — 
CD107a (normal: 207–678 MCF) — 964 — — — 
Triglycerides (normal: <150 mg/dL) — — 194 222 381 
CXCL9 (normal: <12 pg/mL) — — — 122 037 — 
Il-18 (normal: 89–540 pg/mL) — — — 8350 — 

CD107a, cluster of differentiation 107a; CXCL9, chemokine ligand 9; Il-18, interleukin 18; MCF, mean channel fluorescence; WBC, white blood cell count; —, not applicable.

Because of continued concerns for HLH, ferritin was trended and steadily increased during the first 2 weeks of hospitalization, reaching a high of 15 500. Additionally, the patient had mild international normalized ratio elevations and low fibrinogen levels. On hospital day 5, an initial set of laboratory tests to evaluate for HLH revealed increased soluble interleukin-2 receptor, perforin, and granzyme B levels (Table 1). These levels did not meet the diagnostic criteria for HLH (Table 2), and other diagnoses continued to be pursued.

TABLE 2

List of Diagnostic Criteria Used in the Histiocyte Society HLH-2004 Study

(A) Genetic Defect Consistent With HLH or (B) 5 of 8 Clinical and Laboratory Criteria Fulfilled
Fever 
Splenomegaly 
Cytopenia in 2> 3 cell lineages in peripheral blood 
 Hemoglobin <9 g/dL, in neonates <10 g/dL 
 Platelet count <100 × 103/mL 
 Neutrophil count <1 × 103/mL 
Hypertriglyceridemia (>265 mg/dL) or hypofibrinogenemia (<150 mg/dL) 
Hyperferritinemia (>500 ng/mL) 
Soluble CD25 >2400 U/mL (or elevated compared with laboratory-defined normal ranges) 
Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver 
Low or absent NK-cell cytotoxicity 
(A) Genetic Defect Consistent With HLH or (B) 5 of 8 Clinical and Laboratory Criteria Fulfilled
Fever 
Splenomegaly 
Cytopenia in 2> 3 cell lineages in peripheral blood 
 Hemoglobin <9 g/dL, in neonates <10 g/dL 
 Platelet count <100 × 103/mL 
 Neutrophil count <1 × 103/mL 
Hypertriglyceridemia (>265 mg/dL) or hypofibrinogenemia (<150 mg/dL) 
Hyperferritinemia (>500 ng/mL) 
Soluble CD25 >2400 U/mL (or elevated compared with laboratory-defined normal ranges) 
Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver 
Low or absent NK-cell cytotoxicity 

NK, natural killer; CD25, cluster of differentiation 25.

Bone marrow biopsy performed 9 days after admission revealed normocellular marrow with increased hemophagocytic histiocytes, megakaryocytic hyperplasia, and mild megaloblastic changes, negative for malignancy. The patient’s CK increased to a high of 33 983 11 days after admission, and leukopenia, anemia, and thrombocytopenias continued to worsen. An extensive imaging workup was negative, with the exception of abdominal ultrasound revealing mild splenomegaly and MRI of bilateral femurs revealing multifocal edema and swelling consistent with myositis. The patient continued to experience daily fevers, worsening bilateral lower extremity edema, and fatigue. A muscle biopsy of the left rectus guided by MRI findings was obtained. This biopsy specimen revealed relatively focal inflammation and myophagocytosis with occasional necrosis. These biopsy slides were evaluated by a neuromuscular specialist, who felt findings were consistent with regional ischemic immune myopathy, an exceptionally rare condition that has not previously been described in pediatric patients. A comprehensive genetic myositis panel returned negative for any myositis-associated antibodies or specific markers or antibodies, including inflammatory myopathy-associated MDA5 antibody.6 

On hospital day 13, the patient was started on 3-day methylprednisone pulse and anakinra for management of polymyositis and presumed MAS. Methylprednisone was transitioned to 75 mg daily, and he received anakinra 100 mg daily for a total of 12 days. During this treatment, his platelets decreased from 120 to 50, ferritin increased from 4000s to 9000s, CK increased from 4171 to >6000, and cytopenias worsened, necessitating 2 transfusions of packed red blood cells. This lack of improvement prompted repeat bone marrow biopsy and HLH laboratory tests to be obtained. This biopsy specimen revealed hypocellular marrow for age, trilineage hematopoiesis, and profound hemophagocytosis, much worse than previous. Chemokine ligand 9, serum sIL-2, and interleukin-18 laboratory studies were ordered to further elucidate the possibility of HLH (Table 1, day 38). At this time, a genetic panel for primary HLH remained pending, but, given laboratory markers strongly supportive of diagnosis of HLH, directed therapy was initiated with dexamethasone and etoposide.

After initiation of therapy, the patient continued to be intermittently febrile and experience significant lower extremity swelling, neutropenia, and anemia requiring transfusions. Genetic panels for primary sources of HLH or metabolic disease returned negative. Laboratory results 6 days after initiation of dexamethasone and etoposide revealed sIL-2 decrease to 2703.

The patient continued to exhibit significant laboratory abnormalities after 2 weeks of HLH-directed therapy (Table 1, hospital day 59). A repeat comprehensive infectious disease panel was acquired, which was negative. Because of persistent elevations in CK, ferritin, and triglycerides, HLH-directed therapy was discontinued and the patient was started on prednisone 60 mg daily, with improvement in cytopenias. A positron emission tomography–computed tomography (PET-CT) obtained to evaluate for underlying malignancy was negative. The patient felt improved despite persistent laboratory abnormalities and intermittent fever and was discharged after a total of 61 days inpatient. His outpatient medication regimen at discharge included prednisone 60 mg daily and fluconazole, Bactrim, and amoxicillin-clavulanate for infection prophylaxis. He has since been managed closely by pediatric hematology-oncology, rheumatology, and neuromuscular clinics.

HLH is a progressive and severe hyperinflammatory condition with uncontrolled accumulation of macrophages and lymphocytes.1  The secondary form of this condition is often referred to as MAS or reactive HLH. The condition has poor prognosis, regardless of primary or secondary cause: a recent study revealed that malignancy- and nonmalignancy-associated HLH have no significant differences in mean survival time (26.9 ± 3.82 and 35.03 ± 2.19 months, respectively).7  Despite international therapeutic efforts, the 5-year probability of overall survival of pediatric HLH remains 54%.8  The initiation of immunosuppressive and cytotoxic therapy for this syndrome is critical, thus swift, and accurate diagnosis is important. In this case, we highlight the difficulty in diagnosing HLH and initiating appropriate treatment in pediatric patients.

Diagnostic criteria for HLH are variable by group. The most commonly used criteria were developed by the Histiocyte society to define primary HLH in 2004 (Table 2). Despite this, up to 17% of patients with genetically proven HLH do not meet these criteria,9  and many patients will not meet the criteria until late in their disease process.2,10  The symptoms, laboratory findings, and causes of HLH are highly variable and overlap with those of sepsis and systemic inflammatory response syndrome, making diagnosis particularly challenging.1,2,11 

In this case study, the patient initially did not have laboratory values meeting those diagnostic for HLH: increasing ferritin was noted early in the course but not yet to the >10 000 level that has been noted to be more sensitive and specific to HLH.2  ESR and CRP remained within normal range throughout his disease course, further confusing the diagnostic picture. It has been reported that ESR often does not increase in MAS or HLH because of low fibrinogen caused by consumptive coagulopathy, but the absence of elevation in either inflammatory marker is unusual and made determining a potential underlying cause of MAS difficult.12 

Myositis and myopathy are not commonly associated with HLH; however, capillary leak syndrome has been documented in a number of cases of HLH and MAS as well as juvenile dermatomyositis and cytokine storm syndromes.1316  Capillary leak syndrome is a condition in which impaired capillary endothelium and increased vascular permeability lead to symptoms such as edema, hypotension, hypoalbuminemia, and hemoconcentration.1315  This patient did not experience hemoconcentration or hypotension; in fact, his hematocrit was persistently low. However, the edema reported in patients who developed capillary leak syndrome secondary to HLH merits consideration. A less acute form of this syndrome could have contributed to this patient’s otherwise unexplained lower-extremity edema and pain.

A 2020 article reviewing all HLH cases at a large academic medical center over a 10-year period noted that the condition “can be overdiagnosed or underdiagnosed because of lack of defined diagnostic criteria or their incomplete use,” with significant ramifications for patient care.1719  It is entirely possible that the patient described in this report experienced MAS because of a yet undefined primary rheumatologic, immunologic, or infectious cause, and the search for this underlying condition as well as the unusual presentation made effectively treating this patient difficult and delayed. This case further informs clinicians in the consideration of HLH and MAS in early disease course, as well as the difficulties of using laboratory results and the importance of diagnostic flexibility in guiding this diagnosis.

Ms Maloney conceptualized and designed this case report, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Hazra and Baz made substantial contributions to conception and design of this case report and revised the manuscript and critically reviewed it for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

ALT

alanine aminotransferase

AST

aspartate transaminase

CK

creatinine kinase

COVID-19

coronavirus disease 2019

CRP

C-reactive protein

ESR

erythrocyte sedimentation rate

HLH

hemophagocytic lymphohistiocytosis

LDH

lactate dehydrogenase

MAS

macrophage activation syndrome

sIL-2

soluble interleukin 2 receptor

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.