Abstract
A 30-year-old Colombian woman with past history of immune thrombocytopenia (ITP) presented to the emergency room with two days of global headache, arthralgia, myalgia, and low level fever and generalized erythematous rash. Platelets dropped to 9 × 109/L (fourth day of symptoms) without hemorrhagic manifestations but recovered to 30 × 109/L in 24 hours (fifth day). Dengue virus infection, as well as other viral infections, was ruled out. Zika virus (ZIKV) was evaluated in serum and urine samples by real-time reverse-transcriptase polymerase chain reaction (genomic regions within E protein and NS2b protein). Urine sample was positive and serum sample negative for ZIKV, confirming a recent ZIKV infection with urinary tract virus excretion at 7th day after disease onset. To our knowledge this is the first description of a case of severe immune thrombocytopenia exacerbation and antinuclear antibody positivity induced by ZIKV infection.
Introduction
Immune thrombocytopenic purpura (ITP) or immune thrombocytopenia is a chronic autoimmune disease characterized by accelerates platelet destruction or inhibition of their production mediated by antiplatelet autoantibodies. 1 Several studies suggest an association between chronic infections by viruses like human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), or chronic bacterial infections, such as Helicobacter pylori, and ITP development or exacerbation. 2 The role of acute flaviviral infections with demonstrated effect on platelet levels such as Dengue virus (DENV) or the potential role of the recently emerged Zika virus (ZIKV) in patients with autoimmune cytopenias is unknown. This is a case report of a woman with past history of immune thrombocytopenic purpura (ITP) consulting during an acute onset of ZIKV infection complicated with severe thrombocytopenia.
Case report
At the end of March 2016, a 30-year-old woman presented to the emergency room of a third level hospital in Cali, Colombia, with two days of global headache, arthralgia, myalgia, and low level fever (38℃). In the 24 hours previous to admission a generalized erythematous rash appeared. Her past medical history revealed immune thrombocytopenia since the age of 16, with no requirement of treatment due to platelet counts over 50×109/L in the last 5 years (monthly complete blood count and hematology follow-up). Her family medical history was positive for systemic lupus erythematosus (SLE) (mother and aunt), and her twin sister has immune thrombocytopenia also. At admission, she was alert, anicteric, and hemodynamically stable. Her liver and spleen were not palpable. Laboratory findings were as follows: white blood cells 7.13 × 109/L, hemoglobin 14.8 g/dL, and platelet 12 × 109/L; laboratory testing for DENV was negative (IgM, IgG, and NS1 protein). Due to severe thrombocytopenia, the patient was admitted to the intensive care unit (ICU), although there was no evidence of any hemorrhagic manifestation. Platelets dropped to 9 × 109/L (fourth day of symptoms) but recovered to 30 × 109/L in 24 hours (fifth day). After 48 hours of observation platelet count persisted over 60 × 109/L and she was discharged. The patient was evaluated at the Virology Laboratory at Universidad del Valle (seventh day of symptoms). DENV serological and molecular testing was negative. ZIKV was evaluated in serum and urine samples by real-time reverse-transcriptase polymerase chain reaction (TaqMan RT-PCR) assay based on a protocol from Lanciotti and colleagues. 3 Samples were considered positive for ZIKV if the two distinct genomic regions (within E protein and NS2b protein) targeted by the RT-PCR were amplified, urine sample was positive, and serum sample tested negative for ZIKV, confirming a recent ZIKV infection with urinary tract virus excretion at seventh day after disease onset.
The Outpatient Clinical Immunology service reassessed the patient. Markers for chronic infections were negative, evidenced by negative results to hepatitis B surface antigen (HBsAg) and HBV anti-core antibodies, hepatitis CIgG, anti-HAV IgG, anti-Epstein–Barr virus (EBV) antibodies, anti-cytomegalovirus antibodies, and HIV Elisa (fourth generation). Quantitative serum immunoglobulin levels (IgG, IgA, IgE, and IgM) and complement levels were normal. Direct Coombs test was negative, antinuclear antibody showed a speckled pattern positive 1:320 dilutions with nuclear extractable antigens (anti-Ro, La, Sm and RNP) negative; anti-dsDNA (crithialuciliae and micro-ELISA) as well as anticardiolipin and antiphospholipid IgG, IgM, and IgA antibodies were negative. Positive ANA was described for the first time in the patient (sample was taken 6 weeks after ZIKV infection) and currently rheumatology and immunology services follow-up the patient.
Discussion
To our knowledge this is the first description of a case of severe immune thrombocytopenia exacerbation induced by ZIKV infection. An increasing number of studies suggest an association between infectious agents, mainly viral infections and ITP onset. 2 Herpes virus as cytomegalovirus (CMV) has been associated with refractory immune thrombocytopenic purpura, 4 and some authors suggest a change in ITP guidelines management to include evaluation and treatment of herpes virus infection. 5 EBV has been associated with cellular immunity dysfunction characterized by a T helper 2 (Th2) cytokine profile favoring anti-platelet antibodies formation, 6 suggesting a role for chronic viral infections in ITP development. Vaccines as infectious agents can trigger autoimmunity by molecular mimicry, polyclonal activation, bystander activation, or the presence of superantigens. Vaccines can induce autoimmunity not only by antigen immune response but also from excipients of other constituents, residual traces from manufacturing process, adjuvants, or preservatives. 2 However, the role of acute viral infections such as Zika in ITP induction are unknown.
Although flavivirus infections are very frequent in tropical countries, their impact on subjects with ITP or SLE as comorbidity is unknown. A few cases of DENV have been reported exacerbating chronic ITP. DENV infection has been suggested to trigger ITP, 7 or has been related to ITP exacerbation, with variable outcomes, ranging from good clinical response to steroids 8 to fatality, and maybe related to immune suppressive treatment for ITP. 9
The introduction of a new flavivirus, such as ZIKV, represents a challenge for the health care systems worldwide, especially in the Americas and the Caribbean. 10 By April 2016 there were 65,726 cases of ZIKV disease reported in Colombia. 11 Susceptible hosts, such as people living with primary or secondary immunodeficiencies or autoimmune disorders, may have a higher risk than the general population of complications from ZIKV infection. Blood cytopenias have been reported only sporadically in ZIKV disease, and include mild thrombocytopenia (100 × 109–150 × 109 platelets/L), but never moderate or severe thrombocytopenia.12,13 Interestingly although the patient developed a thrombocytopenia lower than 10 × 109 platelets/ L, platelet count recovery was quick and sustained. This case report highlights the necessity of a closer follow up and probably modifications in management guidelines for patients with autoimmune diseases like autoimmune cytopenias or SLE and ZIKV infection, because they may be at higher risk for major complications such as bleeding secondary to severe thrombocytopenia. Our report is a call for action, because emerging flavivirus infections such as ZIKV could represent a trigger for autoimmune diseases such as SLE.
Footnotes
Acknowledgments
We thank all the staff of the laboratory of Virology at the Universidad del Valle and Carlos A Pardo of Neurology at Johns Hopkins University.
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 disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the VIREM research group at Universidad del Valle, Cali, Colombia, funded this research.