• View in gallery

    Time course of serum ferritin levels in the first day after intensive care unit (ICU) admission in a patient with yellow fever. *The patient underwent therapeutic plasma exchange on the second through the fifth days after admission.

  • 1.

    Tuboi SH, Costa ZGA, da Costa Vasconcelos PF, Hatch D, 2007. Clinical and epidemiological characteristics of yellow fever in Brazil: analysis of reported cases 1998–2002. Trans R Soc Trop Med Hyg 101: 169175.

    • Search Google Scholar
    • Export Citation
  • 2.

    Monath TP, Vasconcelos PFC, 2015. Yellow fever. J Clin Virol 64: 160173.

  • 3.

    Monath TP, 2008. Treatment of yellow fever. Antiviral Res 78: 116124.

  • 4.

    Klitting R, Fischer C, Drexler JF, Gould EA, Roiz D, Paupy C, de Lamballerie X, 2018. What does the future hold for yellow fever virus? (II). Genes (Basel) 425.

    • Search Google Scholar
    • Export Citation
  • 5.

    Domingo C, Patel P, Yillah J, Weidmann M, Méndez JA, Nakouné ER, Niedriga M, 2012. Advanced yellow fever virus genome detection in point-of-care facilities and reference laboratories. J Clin Microbiol 50: 40544060.

    • Search Google Scholar
    • Export Citation
  • 6.

    Martin DA, Muth DA, Brown T, Johnson AJ, Karabatsos N, Roehrig JT, 2000. Standardization of immunoglobulin M capture enzyme-linked immunosorbent assays for routine diagnosis of arboviral infections. J Clin Microbiol 38: 18231826.

    • Search Google Scholar
    • Export Citation
  • 7.

    Karvellas CJ, Subramanian RM, 2016. Current evidence for extracorporeal liver support systems in acute liver failure and acute-on-chronic liver failure. Crit Care Clin 32: 439451.

    • Search Google Scholar
    • Export Citation
  • 8.

    Larsen FS 2016. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J Hepatol 64: 6978.

    • Search Google Scholar
    • Export Citation
  • 9.

    van de Weg CA 2014. Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances. PLoS Negl Trop Dis 8: e3214.

    • Search Google Scholar
    • Export Citation
  • 10.

    McElroy AK 2019. Macrophage activation marker soluble CD163 associated with fatal and severe Ebola virus disease in humans. Emerg Infect Dis 25: 290298.

    • Search Google Scholar
    • Export Citation
  • 11.

    Kernan KF, Carcillo JA, 2017. Hyperferritinemia and inflammation. Int Immunol 29: 401409.

  • 12.

    Quaresma JA, Barros VL, Pagliari C, Fernandes ER, Andrade HF, Vasconcelos PF, Duarte MI, 2007. Hepatocyte lesions and cellular immune response in yellow fever infection. Trans R Soc Trop Med Hyg 101: 161168.

    • Search Google Scholar
    • Export Citation
  • 13.

    Quaresma JA, Barros VL, Pagliari C, Fernandes ER, Guedes F, Takakura CF, Andrade HF, Vasconcelos PF, Duarte MI, 2006. Revisiting the liver in human yellow fever: virus-induced apoptosis in hepatocytes associated with TGF-β, TNF-α and NK cells activity. Virology 345: 2230.

    • Search Google Scholar
    • Export Citation
  • 14.

    Quaresma JA, Lima LW, Fuzii HT, Libonati RM, Pagliari C, Duarte MI, 2010. Immunohistochemical evaluation of macrophage activity and its relationship with apoptotic cell death in the polar forms of leprosy. Microb Pathog 49: 135140.

    • Search Google Scholar
    • Export Citation
  • 15.

    Engelmann F 2014. Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. PLoS Negl Trop Dis 8: e3295.

    • Search Google Scholar
    • Export Citation
  • 16.

    Wamala JF 2012. Epidemiological and laboratory characterization of a yellow fever outbreak in northern Uganda, October 2010–January 2011. Int J Infect Dis 16: e536e542.

    • Search Google Scholar
    • Export Citation
  • 17.

    Basler CF, 2017. Molecular pathogenesis of viral hemorrhagic fever. Semin Immunopathol 39: 551561.

  • 18.

    Monath TP, Brinker KR, Chandler FW, Kemp GE, Cropp CB, 1981. Pathophysiologic correlations in a rhesus monkey model of yellow fever with special observations on the acute necrosis of B cell areas of lymphoid tissues. Am J Trop Med Hyg 30: 431443.

    • Search Google Scholar
    • Export Citation
  • 19.

    Demirkol D Turkish Secondary HLH/MAS Critical Care Study Group, 2012. Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment? Crit Care 16: R52.

    • Search Google Scholar
    • Export Citation
  • 20.

    Rosário C, Zandman-Goddard G, Meyron-Holtz EG, D’Cruz DP, Shoenfeld Y, 2013. The hyperferritinemic syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med 11: 185.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Severe Yellow Fever and Extreme Hyperferritinemia Managed with Therapeutic Plasma Exchange

View More View Less
  • 1 Intensive Care Unit, Infectious Diseases Institute Emílio Ribas, São Paulo, Brazil

A 43-year-old man was admitted to the intensive care unit and diagnosed with yellow fever. He presented with refractory bleeding, extreme hyperferritinemia, and multiple organ dysfunction syndrome, requiring renal replacement therapy, mechanical ventilation, and treatment with vasoactive drugs. Because the bleeding did not respond to fresh-frozen plasma administration, the patient received therapeutic plasma exchange, which was accompanied by a marked improvement of the clinical and biochemical parameters, including a significant decline in serum ferritin levels.

INTRODUCTION

Yellow fever is an endemic mosquito-borne viral infection of humans and nonhuman primates in the tropical regions of Africa and South America, currently being a leading cause of hemorrhagic fever-related mortality in those regions.1,2 Infection with the yellow fever virus can result in disseminated disease that is typically characterized by a sudden onset of fever and prostration, the more severe form of yellow fever being associated with hepatic, renal, and myocardial failure, as well as with hemorrhagic diathesis and shock.1,2 The mortality rates associated with yellow fever in South America have been reported to be as high as 60%.2 There is as yet no specific pharmacological treatment for yellow fever. For individuals infected with the yellow fever virus, the treatment remains limited to symptomatic and supportive care, which produces unsatisfactory results in those with the most severe presentations.3,4 Here, we describe a case of multiple organ failure and refractory bleeding in a patient with yellow fever, in whom the disease was successfully managed with therapeutic plasma exchange (TPE).

CASE REPORT

A 43-year-old male rural worker, who had not been vaccinated against yellow fever, presented with a 7-day history of fever, headache, myalgia, malaise, and nausea, together with a 3-day history of abdominal pain, jaundice, and anuria. The patient lived and worked on a peach palm (Bactris gasipaes) farm in the south of the Brazilian state of São Paulo, where there was an ongoing outbreak of yellow fever, and he had not traveled recently. He was admitted to the intensive care unit (ICU). At ICU admission, blood samples were collected and sent for diagnostic tests. The diagnostic hypothesis of yellow fever was confirmed by real-time polymerase chain reaction and serologic testing with immunoglobulin M antibody–capture ELISA (MAC-ELISA; Centers for Disease Control and Prevention, Atlanta, GA).5,6 The patient tested negative for dengue (MAC-ELISA; Centers for Disease Control and Prevention) and viral hepatitis A, B, and C (by electrochemiluminescence). At admission, he was conscious but disoriented, with a heart rate of 64 bpm, blood pressure of 128/97 (103) mmHg, respiratory rate of 12 bpm, peripheral oxygen saturation on room air of 91%, axillary temperature of 36°C, ecchymoses on the arms, gingival bleeding, asterixis (flapping tremor), and anuria. Soon after ICU admission, he presented generalized tonic–clonic seizures, which were controlled with midazolam, and he was intubated because mechanical ventilation was necessary. He also evolved to hypotension, requiring saline infusion, as well as administration of sodium bicarbonate and norepinephrine, to maintain the target mean arterial pressure of 65 mmHg. Blood was drawn for laboratory tests (Table 1), and he was started on renal replacement therapy (hemodialysis). He subsequently developed massive bleeding through the nasogastric tube and from the puncture sites. The bleeding was refractory to fresh-frozen plasma infusion and required packed red cell transfusion. Therefore, beginning on day 2 after ICU admission, he was submitted to TPE once daily for four consecutive days, with no fixed time interval between the sessions—at a rate of 1 L/h, plasma was removed and replaced with an equivalent volume of fresh-frozen plasma; the total volume of plasma exchanged was 3 L/day. On the third day of TPE, the spontaneous bleeding decreased, and the vasoactive drugs were discontinued on the following day. The blood tests performed at admission had also revealed hyperferritinemia, and there was a progressive decline in ferritin levels from the first TPE session onward (Figure 1), just as there were improvements in most of the biochemical parameters and in the sequential organ failure assessment score (Table 1). The patient was extubated on day 8 and showed no subsequent bleeding. He was discharged from ICU 40 days after admission.

Table 1

Biochemical findings and sequential organ failure assessment score during the first week in the intensive care unit

VariableD1D2*D3*D4*D5*D6D7Normal range
Hemoglobin11.06.77.04.26.68.27.613–16 g/dL
Hematocrit3428.119.310.916.4222037–49%
White blood cells16,40014,10019,10018,00014,90018,80016,0004,500–13,500/µL
Platelets1008991101614062150–400 × 103/µL
C-reactive protein11.930.882.569.4394634< 5 mg/L
Ferritin> 100,00075,58156,65621,222NDNDND30–400 ng/mL
Alanine aminotransferase5,8902,99756025615011110310–49 U/L
Aspartate aminotransferase2,8501,4801,170576345257216< 34 U/L
Lactate dehydrogenase7,6205,4253,0281,8551,4131,031706100–190 U/L
Total bilirubin39.038.641.441.3244.441.522.4≤ 1.0 mg/dL
Direct bilirubin23.023.925.826.8729.628.015.8≤ 0.7 mg/dL
Ammonia258ND78NDNDNDND11–32 μmol/L
International normalized ratio1.51.281.411.151.12ND1.00.95–1.12
Fibrinogen141106205210334ND322200–400 mg/dL
Factor V1441158010312015716462–139%
Urea209108805372677810–50 mg/dL
Creatinine16.410.78.415.897.65.985.290.7–1.2 mg/dL
Sodium136139135134134135135135–145 mEq/L
Potassium4.44.74.53.73.34.33.53.5–5.0 mEq/L
Bicarbonate6.225212625.8242622–26 mmol/L
Lactate1182337211111104.5–14.4 mg/dL
Glucose9711214017194168120≤ 99 mg/dL
Amylase297765719676661470452< 125 U/L
Lipase3305981,1131,924ND4583358–78 U/L
Sequential organ failure assessment score17151714141714

D = day; ND = no data.

* Days on which the patient underwent therapeutic plasma exchange.

Figure 1.
Figure 1.

Time course of serum ferritin levels in the first day after intensive care unit (ICU) admission in a patient with yellow fever. *The patient underwent therapeutic plasma exchange on the second through the fifth days after admission.

Citation: The American Journal of Tropical Medicine and Hygiene 101, 3; 10.4269/ajtmh.19-0219

DISCUSSION

Hepatic failure and renal failure are hallmarks of severe, life-threatening yellow fever, as is bleeding diathesis. In a retrospective cohort study of patients with yellow fever, Tuboi et al.1 found that the following factors were associated with higher mortality in their univariate analysis: male gender; age > 40 years; jaundice; serum aspartate aminotransferase > 1,200 IU/L; alanine aminotransferase > 1,500 IU/L; total bilirubin > 7.0 mg/dL; direct bilirubin > 5.0 mg/dL; and blood urea nitrogen > 100 mg/dL. Those authors reported that elevated aspartate aminotransferase and jaundice both remained independently associated with higher mortality in their multivariate analysis. In the case presented here, the patient had all of those risk factors at admission, subsequently evolving to shock, metabolic acidosis, hyperlactatemia, and refractory bleeding, which are indicative of a grim prognosis.

In the present case of yellow fever virus infection, the initial support therapies for the acute hepatic and renal failure included hemodialysis, transfusion of packed red cells, and infusion of fresh-frozen plasma. However, the administration of the blood products failed to control the bleeding. Our decision to use TPE, in which the patient plasma is replaced with fresh plasma, was based on previous reports of its successful use in patients with fulminant hepatic failure.7,8 In this context, TPE has been shown to increase survival by providing significant improvements in multiple clinical parameters, such as liver enzymes, renal function, lactate (as a marker of tissue injury), and the model for end-stage liver disease score.7,8 The remarkable improvement observed in our patient, whose initial prognosis was dismal, is the cause for optimism regarding the potential role of TPE as a useful treatment in refractory cases of yellow fever.

Another remarkable finding in the case presented here was the extremely high level of ferritin (> 100,000 ng/mL [normal range 30–400 ng/mL]) at ICU admission. Although hyperferritinemia has been reported in other viral hemorrhagic fevers, such as dengue and Ebola,9,10 this is, to our knowledge, the first time it has been reported in yellow fever. The pathogenesis of the hyperferritinemia in our patient was probably multifactorial. Hepatocytes, Kupffer cells, proximal tubular renal cells, and macrophages have all been shown to secrete ferritin under various in vivo and in vitro conditions,11 and it is noteworthy that our patient presented with severe hepatic and renal injury. Cultured cells have also been shown to release ferritin into surrounding media when grown in the presence of interleukin 1 beta or tumor necrosis factor alpha,11 cytokines that are known to be elevated during infection with the yellow fever virus.12,13

Involvement of the liver and kidneys, together with the potential increase in macrophage activity during infection with the yellow fever virus,12,14 suggests that ferritin could be a biomarker of severity and prognosis and that the determination of ferritin levels could be a practical tool to monitor disease progression in YF. In addition, ferritin plays a role in the pathogenesis of inflammatory diseases by modulating the innate immune response and lymphocyte function. In humans, T and B lymphocytes bind ferritin, directly eliciting an immunosuppressive effect through impairment of T-cell proliferation, B-cell maturation, and immunoglobulin production. Severe lymphocyte impairment is a characteristic of severe YF in humans and in experimentally infected macaques.1518 The potential role of ferritin in such derangement offers a rationale to consider therapeutic measures aimed at its clearance.19,20

In the case presented here, the post-TPE improvement in synthetic and metabolic liver function was clinically evident and eventually resulted in normalization of the international normalized ratio and effective control of the bleeding diathesis. That improvement was accompanied by a progressive decrease in the plasma ferritin levels. It remains unclear whether this kinetic behavior of ferritin mirrors its role as a sensitive biomarker of inflammation and liver/kidney damage, thus reflecting the clinical improvement, or whether the removal of ferritin by TPE played a role in bringing about that improvement. The role of ferritin (in the pathogenesis of disease and as a biomarker of severity) merits further study, as does the role of TPE in the management of cases such as the one presented here.

REFERENCES

  • 1.

    Tuboi SH, Costa ZGA, da Costa Vasconcelos PF, Hatch D, 2007. Clinical and epidemiological characteristics of yellow fever in Brazil: analysis of reported cases 1998–2002. Trans R Soc Trop Med Hyg 101: 169175.

    • Search Google Scholar
    • Export Citation
  • 2.

    Monath TP, Vasconcelos PFC, 2015. Yellow fever. J Clin Virol 64: 160173.

  • 3.

    Monath TP, 2008. Treatment of yellow fever. Antiviral Res 78: 116124.

  • 4.

    Klitting R, Fischer C, Drexler JF, Gould EA, Roiz D, Paupy C, de Lamballerie X, 2018. What does the future hold for yellow fever virus? (II). Genes (Basel) 425.

    • Search Google Scholar
    • Export Citation
  • 5.

    Domingo C, Patel P, Yillah J, Weidmann M, Méndez JA, Nakouné ER, Niedriga M, 2012. Advanced yellow fever virus genome detection in point-of-care facilities and reference laboratories. J Clin Microbiol 50: 40544060.

    • Search Google Scholar
    • Export Citation
  • 6.

    Martin DA, Muth DA, Brown T, Johnson AJ, Karabatsos N, Roehrig JT, 2000. Standardization of immunoglobulin M capture enzyme-linked immunosorbent assays for routine diagnosis of arboviral infections. J Clin Microbiol 38: 18231826.

    • Search Google Scholar
    • Export Citation
  • 7.

    Karvellas CJ, Subramanian RM, 2016. Current evidence for extracorporeal liver support systems in acute liver failure and acute-on-chronic liver failure. Crit Care Clin 32: 439451.

    • Search Google Scholar
    • Export Citation
  • 8.

    Larsen FS 2016. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J Hepatol 64: 6978.

    • Search Google Scholar
    • Export Citation
  • 9.

    van de Weg CA 2014. Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances. PLoS Negl Trop Dis 8: e3214.

    • Search Google Scholar
    • Export Citation
  • 10.

    McElroy AK 2019. Macrophage activation marker soluble CD163 associated with fatal and severe Ebola virus disease in humans. Emerg Infect Dis 25: 290298.

    • Search Google Scholar
    • Export Citation
  • 11.

    Kernan KF, Carcillo JA, 2017. Hyperferritinemia and inflammation. Int Immunol 29: 401409.

  • 12.

    Quaresma JA, Barros VL, Pagliari C, Fernandes ER, Andrade HF, Vasconcelos PF, Duarte MI, 2007. Hepatocyte lesions and cellular immune response in yellow fever infection. Trans R Soc Trop Med Hyg 101: 161168.

    • Search Google Scholar
    • Export Citation
  • 13.

    Quaresma JA, Barros VL, Pagliari C, Fernandes ER, Guedes F, Takakura CF, Andrade HF, Vasconcelos PF, Duarte MI, 2006. Revisiting the liver in human yellow fever: virus-induced apoptosis in hepatocytes associated with TGF-β, TNF-α and NK cells activity. Virology 345: 2230.

    • Search Google Scholar
    • Export Citation
  • 14.

    Quaresma JA, Lima LW, Fuzii HT, Libonati RM, Pagliari C, Duarte MI, 2010. Immunohistochemical evaluation of macrophage activity and its relationship with apoptotic cell death in the polar forms of leprosy. Microb Pathog 49: 135140.

    • Search Google Scholar
    • Export Citation
  • 15.

    Engelmann F 2014. Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. PLoS Negl Trop Dis 8: e3295.

    • Search Google Scholar
    • Export Citation
  • 16.

    Wamala JF 2012. Epidemiological and laboratory characterization of a yellow fever outbreak in northern Uganda, October 2010–January 2011. Int J Infect Dis 16: e536e542.

    • Search Google Scholar
    • Export Citation
  • 17.

    Basler CF, 2017. Molecular pathogenesis of viral hemorrhagic fever. Semin Immunopathol 39: 551561.

  • 18.

    Monath TP, Brinker KR, Chandler FW, Kemp GE, Cropp CB, 1981. Pathophysiologic correlations in a rhesus monkey model of yellow fever with special observations on the acute necrosis of B cell areas of lymphoid tissues. Am J Trop Med Hyg 30: 431443.

    • Search Google Scholar
    • Export Citation
  • 19.

    Demirkol D Turkish Secondary HLH/MAS Critical Care Study Group, 2012. Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment? Crit Care 16: R52.

    • Search Google Scholar
    • Export Citation
  • 20.

    Rosário C, Zandman-Goddard G, Meyron-Holtz EG, D’Cruz DP, Shoenfeld Y, 2013. The hyperferritinemic syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med 11: 185.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Jaques Sztajnbok, Intensive Care Unit, Infectious Diseases Institute Emílio Ribas, Rua Cristiano Viana 765, ap:32; CEP 05411-001, São Paulo, Brazil. E-mail: jaques.sztajnbok@gmail.com

Authors’ addresses: Jaques Sztajnbok, Ceila Maria Sant’Ana Malaque, Camila Hitomi Nihei, Irene Faria Duayer, Zita Maria Leme Britto, Eduarda Gambini Beraldo, and Ralcyon Francis AzevedoTeixeira, Emílio Ribas Institute of Infectious Diseases, São Paulo, Brazil, E-mails: jaques.sztajnbok@gmail.com, ceila.malaque@emilioribas.sp.gov.br, camila.nihei@emilioribas.sp.gov.br, irene.duayer@emilioribas.sp.gov.br, zita.britto@emilioribas.sp.gov.br, eduardagambiniberaldo@gmail.com, and ralcyon.teixeira@emilioribas.sp.gov.br.

Save