Acute HIV infection presenting as hemophagocytic lymphohistiocytosis: case report and review of the literature
© The Author(s). 2017
Received: 23 March 2017
Accepted: 12 September 2017
Published: 20 September 2017
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© The Author(s). 2017
Received: 23 March 2017
Accepted: 12 September 2017
Published: 20 September 2017
Hemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory condition that can result from infections, autoimmune diseases and malignancies. It is a rarely reported life threatening complication of an acute HIV infection, with only ten documented case reports per our literature search. We present a case of HLH secondary to acute HIV infection with a negative HIV antibody-based assay and high plasma viral load.
A 45 year old male with a past medical history of well controlled hypertension presented with fever, dizziness and non-bloody diarrhea. Initial lab work revealed a new thrombocytopenia, marked renal failure and an elevated creatine kinase, ferritin, lactate dehydrogenase and D-dimer. A bone marrow biopsy revealed HLH. As part of the work up for thrombocytopenia, a rapid HIV antibody based assay was done and was negative. The sample was later routinely tested with a fourth generation antigen/antibody assay as per local protocol and was strongly positive. The plasma RNA viral load was >10,000,000 copies /mL confirming the diagnosis of an acute HIV infection. The patient was urgently started on antiretroviral therapy and recovered.
This case illustrates a diagnostic approach to HLH which is an uncommon but life threatening multisystem disease, requiring the involvement of a multidisciplinary team of experts. Following any diagnosis of HLH, rapid identification and treatment of the underlying condition is critical. A negative rapid HIV antibody test can be misleading in the context of early HIV infection and the additional use of fourth generation antigen/antibody test or plasma RNA viral load may be required within the right clinical context for diagnosis.
Differential diagnosis of secondary hemophagocytic lymphohistiocytosis 
Epstein-Barr Virus, Cytomegalovirus, Parvovirus, Herpes Simplex Virus, Varicella-Zoster Virus, Measles, Human Herpes Virus-8, H1N1 Influenza Virus, Parechovirus, HIV
Brucella spp., Gram negative bacteria, Mycobacterium tuberculosis, Staphylococcus aureus,
Candida, Cryptococcus, Pneumocystis, Histoplasma, Aspergillus
Plasmodium falciparum, Plasmodium vivax, Toxoplasma, Leishmania, Strongyloides
Systemic juvenile idiopathic arthritis, Kawasaki’s disease systemic lupus erythematosus and other rheumatologic diseases
T-cell/NK-cell lymphomas, anaplastic large cell lymphomas, acute lymphoblastic leukemia, Hodgkin’s lymphoma, various solid tumours (prostate, lung, hepatocellular carcinoma)
Inherited or acquired immunodeficiency
A middle aged man with a history of controlled hypertension presented with a one week history of non-bloody diarrhea with fever and dizziness. He reported four to six non-bloody bowel movements a day for the one week prior to admission with subjective fevers and a sore throat. He reported being in a monogamous relationship with his wife and denied use of any illicit intravenous or oral drugs, alcohol or recent travel outside Canada.
Examination revealed a fever of 38.0 °C, heart rate of 76, blood pressure of 163/100 and a respiratory rate of 16 with saturations of 93% on room air. He had erythematous tonsils with no exudate and a clinical diagnosis of oral candidiasis. There was no rash, palpable lymphadenopathy or oral ulcers but he had mild bleeding of his gums. He had a fluctuant mass on his left upper thigh with purulent drainage. The rest of his exam was unremarkable.
Laboratory values at presentation and after treatment
Patient lab values
After 5 weeks of antiretroviral therapy
White blood cell, ×109/L
Total bilirubin, μmol/L
Lactate Dehydrogenase (LDH), U/L
Creatine kinase, U/L
CD4 Count, ×109/L
Viral load, copies/mL
>7.24 log base 10
1.96 log base 10
HIV Architect 4th generation assay
The sample submitted for rapid HIV testing was later routinely tested with a fourth generation antigen/antibody assay (Abbott Architect, Abbott Illinois USA) as per local protocol. The test was strongly positive with a signal to cut off ratio of 615.18 (Normal <1) and the Western blot showed no antibody bands. The plasma RNA viral load was >10,000,000 copies/mL (Abbott Realtime Illinois USA), confirming the diagnosis of acute HIV infection. His CD4 count was low at 0.137 × 109/L (normal 0.499–1.651 × 109/L).
A diagnosis of acute HIV infection with secondary HLH was made based on criteria from the HLH-2004 trial . A secondary diagnosis of acute kidney injury secondary to rhabdomyolysis occurring in association with the acute HIV seroconversion illness was also made. The MRSA bacteremia was secondary to a subcutaneous abscess in his upper left thigh and the S. mitis bacteremia was thought to be secondary to the bleeding gums as a portal of entry. He was immediately started on an anti-retroviral therapy (ART) regimen consisting of lamivudine 300 mg once daily, dolutegravir 50 mg once daily and rilpivirine 25 mg once daily,based on his overall findings, local resistance patterns to first generation non-nucleoside reverse transcriptase inhibitors and the desire for rapid drop in viral load given the underlying manifestations of his HIV infection.
After five weeks of ART, the plasma RNA viral load had decreased to less than 100 copies/mL and his CD4+ count had increased to 0.275 × 109/L. His platelets, CK, ferritin and creatinine normalized. He responded well to two weeks of intravenous vancomycin and remained adherent to ART. The risk factor for HIV infection remains unclear. By three months follow up, he had developed a full band profile of antibodies to HIV on Western blotting, the viral load was undetectable and all other results had normalized.
Acute HIV infection may be asymptomatic in about half of patients . Symptomatic acute HIV infection presents with nonspecific features such as fever, pharyngitis, lymphadenopathy, a diffuse maculopapular rash, myalgia and malaise although other atypical presentations have been described in the literature .
The diagnosis of HLH can be made based on criteria from the HLH-2004 trial but is difficult to diagnose clinically with a broad differential diagnosis including infections, neoplasms, inflammatory disorders and immunodeficiencies (Table 1) .
HLH is a rare presentation of an acute HIV infection; based on a literature search of articles in English, we were able to find 10 documented cases of adults who presented with HLH secondary to an acute HIV infection [5–12]. Due to its rarity, diagnosis is often difficult, delaying treatment. In this case, a markedly elevated ferritin increased suspicion for HLH which, along with the thrombocytopenia, prompted a bone marrow biopsy. As part of the work up for an underlying cause of HLH, a rapid HIV assay was ordered which was negative. All HIV antibody tests are known to miss the “window period” of acute HIV infection between infection and antibody production . As such, fourth generation antigen/antibody assays along with plasma viral load must be used for diagnosis as per Centers for Disease Control and Prevention guidelines .
In cases of secondary HLH, no immunomodulators are used but rather treatment of the primary condition is given to control the acute inflammatory cascade that results in HLH. We used no immunomodulatory therapy and chose, in the absence of resistance testing, an empiric regimen to suppress viremia rapidly in an effort to reduce the active HLH related co-morbidities.
This case report suggests that acute HIV infection needs to be considered when the cause of HLH is not apparent. While rapid HIV antibody testing is fast and easily accessible, its limitations in diagnosis of early HIV need to be acknowledged as it cannot be used to exclude acute infection prior to the antibody response. The value of solid testing algorithms and use of fourth generation antigen-antibody assays with molecular testing for a definitive diagnosis are affirmed by this case. With HLH, consideration of all its etiologies with appropriate diagnostic testing is required. While the differential for secondary HLH is broad, consideration of the clinical context can help dictate what kind of testing needs to be done.
HLH as a presentation of acute HIV infection is rare and potentially life threatening. HLH is a complex multisystem disease and requires the involvement of different disciplines including experts in the fields of infectious diseases, hematology, immunology and pathology for diagnosis and management. Following any diagnosis of HLH, rapid identification and treatment of the underlying condition is critical. Our case suggests that a negative rapid HIV antibody test can be misleading in the context of early HIV infection and the additional use of fourth generation antigen/antibody test or plasma RNA viral load may be required within the right clinical context for diagnosis.
Human immunodeficiency virus
The authors would like to thank Dr. Kevin Fonseca, ProvLab Alberta, Alberta Health Services and at the University of Calgary for his guidance and interpretation of the virology data.
This case report was not funded.
FM did the literature search and wrote up the first draft of the case report. EW assisted in the decision making for the management of the case and was involved in providing guidance and editing of the manuscript. EM was responsible for the hematopathology assessment and interpretation and providing guidance and editing of the manuscript. JG and JC were senior authors and were involved in the decision making for the management of the case, interpreting the results of the laboratory testing, editing and providing their expertise. All authors approved of the final edited manuscript.
Consent has been obtained from the patient for the publishing of this case report and any accompanying data. Additionally, consent has been obtained for the publishing of images from his bone marrow biopsy. This consent has been explicitly documented in the patient’s clinical chart.
The authors declare that they have no competing interests.
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