Reactive hemophagocytic syndrome in the setting of acute human immunodeficiency virus 1 infection: case report and review of the literature

Abstract

We report a case of reactive hemophagocytic syndrome (RHS) in the setting of acute human immunodeficiency virus type 1 infection (AHI). In addition, we review 11 previously reported cases of RHS precipitated by AHI and discuss strategies in the diagnosis and management of these overlapping clinical entities.

Keywords

Reactive hemophagocytic syndrome human immunodeficiency virus

Introduction

Hemophagocytic syndrome (HPS) is a life-threatening condition caused by a disproportionate and dysregulated immune response. There are two major forms of HPS: the primary form, hereditary HPS, occurs in infancy and is caused by a variety of genetic abnormalities. The secondary form, reactive hemophagocytic syndrome (RHS), occurs at any age due to infections, malignancies, and rheumatologic conditions. Only a few case reports have detailed the development of RHS in the setting of acute human immunodeficiency virus type 1 infection (AHI).¹ We report one such case and review 11 similar cases reported in the literature.

Case report

A young man in his 20s was admitted with fever, altered mental status, and a diffuse maculopapular rash. Thirteen days earlier, he had been diagnosed with AHI after presenting with a nonspecific febrile illness, a positive HIV antigen/antibody assay, and a negative HIV-1/2 antibody differentiation assay. Since his fever initially resolved, the patient deferred initiation of antiretroviral therapy (ART) until after the results of a pending HIV-1 viral load. However, a few days later, his fever returned, and he became lethargic and developed mild disorientation (to date only), headache, nausea, vomiting, and a syncopal episode that prompted hospitalization. His vital signs were significant for a fever of 41°C and mild tachycardia. He appeared somnolent, tremulous, and had a diffuse, evanescent, erythematous maculopapular rash. Laboratory studies revealed a leukocyte count of 4000 per mcl, hematocrit of 24.9%, platelet count of 56,000 per mcl, aspartate aminotransferase (AST) of 598 IU/l, alanine aminotransferase of 302 IU/l, triglycerides of 559 mg/dl, ferritin of greater than 36,000 ng/ml, and fibrinogen of 271 mg/dl. CD4 cell count was 248 cells/mm³ (48%). HIV-1 viral load was 9.7 million copies per milliliter. Epstein–Barr virus-specific immunoglobulins and mild viremia of 592 copies per ml were consistent with previous infection. Serologic testing for atypical bacteria and opportunistic fungi was negative. Lumbar puncture revealed an elevated cerebrospinal fluid (CSF) protein (135 mg/dl) but no CSF pleocytosis or hypoglycorrhachia. CSF bacterial, fungal, and mycobacterial cultures; herpes and enterovirus virus polymerase chain reaction; West Nile Virus immunoglobulins; Venereal Disease Research Laboratory test; and cryptococcal antigen were negative (Table 1). Magnetic resonance imaging of the brain did not reveal any abnormalities. Computed tomography scan of the chest, abdomen, and pelvis revealed a spleen in the upper limits of normal in size, and prominent subcarinal, axillary, and mediastinal lymph nodes that did not meet radiologic size criteria for lymphadenopathy. The patient was started on dolutegravir and emtricitabine–tenofovir disoproxil fumarate. In addition, a bone marrow biopsy revealed histiocytosis and prominent hemophagocytosis (Figure 1). Due to the suspicion of RHS with neurologic involvement, the patient was started on systemic corticosteroids and etoposide, and intrathecal methotrexate one day after starting ART. The patient defervesced and returned to his baseline mental status by the time of discharge three days later. The patient remained on ART and his HIV-1 viral load became undetectable within four months. He completed treatment for presumed RHS without any adverse effects.

Table 1.

Timeline of diagnostic studies and therapies.

Diagnostic study	Day 0^a	Day 12	Day 13Start DTG+TDF/FTC	Day 14Start CS+Etoposide, IT MTX	Day 32
Serum^b
CD4 cell count (%)	248 (45%)				538/44%
HIV-1 RNA (copies/ml)	9.7M				1,139 (day 59)
Ferritin (ng/ml)	3, 366	>36,000			623
WBC/Hgb (g/dl)/Plt	4.3/14/108	4/9/56			4/9.8/254
AST/ALT/ALP/TB	24/16/40/0.8	598/302/795/4.2			23/53/77/0.7
Triglycerides (mg/dl)	163	271			199 (day20)
Fibrinogen (mg/dl)	465	559			216 (day 26)
EBV VCA IgG	POS
EBV VCA IgM	NEG
EBV nuclear antigen IgG	POS
EBV DNA (copies/ml)		592
Influenza/RSV (nasopharyngeal) PCR	NEG
HAV/HBV/HCV serologies		Susceptible
WNV IgG/IgM	NEG/NEG
Bartonella DNA	NEG
Brucella IgG/IgM	NEG/NEG
Rickettsia typhi IgG/IgM	NEG/NEG
RPR	1:1
Cryptococcus antigen		NEG
Histoplasma (urine) antigen		NEG
Toxoplasma IgG/IgM		NEG/NEG
CSF
WBC/glucose/protein		0/42/135			0/61/38
HSV1/2 PCR		NEG
VZV PCR		NEG
CMV PCR		NEG
HHV6 PCR		NEG
Enterovirus PCR		NEG
WNV IgG/IgM		NEG/NEG
JCV PCR		NEG
VDRL		NEG
Cryptococcus antigen		NEG
Cytology		No malignant cells			No malignant cells
Bone marrow biopsy		See Figure 1 (day 13)

ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CMV: cytomegalovirus; CS: corticosteroids; DTG: dolutegravir; EBV: Epstein–Barr virus; FTC: emtricitabine; HAV: hepatitis A virus; HBV: hepatitis B virus; HCV: hepatitis C virus; HHV6: human herpes virus 6; HSV: herpes simplex virus; IT MTX: intrathecal methotrexate; JCV: John Cunningham virus; NEG: negative, not detected, or nonreactive; PCR: polymerase chain reaction; RPR: rapid plasma reagin; RSV: respiratory syncytial virus; TB: total bilirubin; TDF: tenofovir disoproxil fumarate; VCA: viral capsid antigen; VDRL: Venereal Disease Research Laboratory test; VZV: varicella zoster virus; WBC: white blood cell; WNV: West Nile virus.

^aDay 0 is the day of initial presentation for acute HIV-1 infection.

^bCollected from serum unless otherwise specified.

Abnormal results are highlighted in bold print.

Figure 1.

Bone marrow aspirate showing hemophagocyte (arrow) at 100X magnification. Source: Photo courtesy of Hongying Tina Tan, MD, PhD, OVMC-UCLA Pathology Department.

Discussion

Most of our understanding of the pathophysiology of HPS comes from studying the genetic abnormalities responsible for hereditary HPS. These mutations impair the activity of natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). The dysfunctional NK cells and CTLs are produced in greater numbers and lead to the disproportionate secretion of cytokines and hyperstimulation of macrophages that are responsible for the clinical features of HPS.¹ Interestingly, stimulation of NK cells and CTLs, and precipitation of a cytokine storm by ramp-up viremia are early events in the pathophysiology of HIV-1 infection.² The latest iteration of the Histiocyte Society’s diagnostic criteria for HPS assigns a point each for fever ≥38.5°C, splenomegaly, ≥2 cytopenias, ferritin ≥500 ng/ml, triglycerides ≥265 mg/dl, fibrinogen ≤150 mg/dl, and hemophagocytosis.³ The recently introduced H-score, which was validated specifically for RHS, refines these cutoffs and adds points for underlying immunosuppression, hepatomegaly, and AST ≥30 IU/l.⁴ Fever, organomegaly, and increased transaminases are frequently observed in AHI.² Ferritin, triglycerides, and fibrinogen are nonspecific acute-phase reactants and are usually abnormal in the setting of inflammation due to any cause although perhaps not to the degree that they are in HPS. Hemophagocytosis is also nonspecific and encountered frequently in HIV-1-infected patients. Our case and the 11 previously reported cases (Table 2) highlight the overlapping symptomatology of these clinical processes and raise important questions regarding the management of patients suspected of being affected by both: Is it appropriate to start ART in this setting? Is immunomodulatory therapy necessary once ART has been started? Several studies have shown that starting ART during AHI may minimize the size and heterogeneity of the latent viral reservoir and optimize the probability of complete immune reconstitution.¹⁴ Furthermore, it appears that a high HIV-1 viral load may be a contributing factor in the pathogenesis of AHI-associated RHS (Table 3). Therefore, rapidly reducing the concentration of circulating virus may interrupt the runaway immune response and symptomatology of AHI-associated RHS. Immunomodulators were used in four of the reported cases (Table 3) but their benefit is unclear at best since all patients survived regardless of immunomodulatory therapy. Treating the precipitant is likely the key step in interrupting the inflammatory cascade. It could be argued that after a certain point, it may be too late to arrest the runaway immune response without immunomodulators but their use in AHI-associated RHS should be limited to cases in which symptoms persist despite prompt initiation of ART. RHS in the setting of AHI is a potentially life-threating phenomenon. Prompt initiation of ART with or without judicious coadministration of immunomodulators in selected cases appears to be a safe and potentially beneficial management strategy.

Table 2.

Clinical features of reported cases.

Reference	Age/gender	CD4 cell count (cells/mm³)/VL (copy/ml)	Fever	Rash	HS/SM	WBC/Hgb/Plt	TG (mg/dl)	AST (IU/l)/ALT (IU/l)	Ferritin (ng/ml)	Fibrinogen (mg/dl)	HPC
Pellegrin et al.⁵	27/M	500/NR	Y	NR	Y/Y	10/10.9/194	NR	NR	NR	NR	LN/Y
Pontes et al.⁶	28/F	NR/NR	Y	NR	Y/N	1.4/12.2/70	NR	NR	NR	NR	BM/Y
Martínez-Escribano et al.⁷	31/M	300/?	Y	Y	Y/N	1.6/9/94	NR	Elevated	NR	NR	LN/Y
Chen et al.⁸	18/M	63/5.7 log10	Y	NR	N/Y	2.8/14.7/90	184	NR	17,010	NR	BM/YLN/Y
Concetta et al.⁹	27/M	138/27M	Y	Y	Y/Y	3.4/9.8/?	NR	NR/468	NR	NR	LN/Y
Sun et al.¹⁰	31/M	324/5.9 log10	Y	NR	N/Y	5.8/11.3/12	182	NR	4,625	NR	BM/Y
Sun et al.¹⁰	23/M	194/5.9 log10	Y	NR	N/Y	2.2/13/102	168	NR	2,227	NR	BM/Y
Sun et al.¹⁰	25/M	191/5.9 log10	Y	NR	Y/Y	1.6/15.7/59	99	NR	29,893	NR	BM/Y
Park et al.¹¹	44/M	157/>10⁹	Y	Y	Y/N	3.9/13.6/90	480	494/869	>30,000	178	BM/Y
Adachi et al.¹²	48/M	276/3M	Y	Y	N/N	2.5/10/88	332	438/162	34,192	NR	BM/Y
Ferraz et al.¹³	27/F	13/384,687	Y	N	NR/NR	1.7/7.9/88	254	153/80	2095	114	BM/Y
PS	23/M	248/9.7M	Y	Y	N/Y	4/8.3/56	559	618/299	>36,000	261	BM/Y

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BM: bone marrow biopsy; F: female; HPC: Hemophagocytosis; HS: hepatosplenomegaly; LN: lymph node biopsy; M: male; N: no; NR: not reported; PS: present study; SM: splenomegaly; TG: triglycerides; VL: viral load; Y: yes.

Table 3.

Treatment and outcome of reported cases.

Reference	Age/gender	Opportunistic infection	ART	Days from onset: ART	Immunomodulatory Rx	Other treatment	Outcome
Pellegrin et al.⁵	27/M	None	None	NR	None	None	Survived
Pontes et al.⁶	28/F	Oral candidiasis	None	NR	None	APAP, ketoconazole	Survived
Martínez-Escribano et al.⁷	31/M	Esophageal candidiasis	None	NR	CS	Fluconazole	Survived
Chen et al.⁸	18/M	None	Y	84	None	IVIG, abx	Survived
Concetta et al.⁹	27/M	Oral candidiasis	Zidovudine, lamivudine, lopinavir/ritonavir	11	None	None	Survived
Sun et al.¹⁰	31/M	Oral candidiasis	None	NR	CS	IVIG, abx, fluconazole	Survived
Sun et al.¹⁰	23/M	Oral candidiasis	None	NR	None	IVIG, fluconazole	Survived
Sun et al.¹⁰	25/M	Oral candidiasis	None	NR	None	Abx, fluconazole	Survived
Park et al.¹¹	44/M	None	Zidovudine, lamivudine, indinavir	21	None	None	Survived
Adachi et al.¹²	48/M	Oral candidiasis	RAL, FTC/TDF → RAL, abacavir/lamivudine	25	None	Cefotaxime	Survived
Ferraz et al.¹³	27/F	Oral candidiasis	ATV/r, FTC/TDF → RAL, FTC/TDF → DRV/r, ETV, FTC/TDF	34	CS	None	Survived
PS	23/M	None	Dolutegravir, FTC/TDF	15	CS, etoposide, IT MTX	Acyclovir, ampicillin, CTX	Survived

Abx: unspecified antibacterials; APAP: Acetaminophen; ART: antiretroviral therapy; ATV/r: Atazanavir/ritonavir; CS: corticosteroids; CTX: ceftriaxone; DRV/r: ritonavir-boosted darunavir; ETV: etravirine; F: female; FTC: emtricitabine; IT MTX: intrathecal methotrexate; IVIG: intravenous immunoglobulin; M: male; N: no; NR: not reported; RAL: raltegravir; TDF: tenofovir tenofovir disoproxil fumarate; Y: yes.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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