Show Summary Details
Page of

Diagnosis and management of viral haemorrhagic fevers in the ICU 

Diagnosis and management of viral haemorrhagic fevers in the ICU
Chapter:
Diagnosis and management of viral haemorrhagic fevers in the ICU
Author(s):

Emersom C. Mesquita

and Fernando A. Bozza

DOI:
10.1093/med/9780199600830.003.0293
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2020. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

date: 30 November 2020

Key points

  • Always suspect viral haemorrhagic fevers (VHFs) in a sick traveller from an endemic area in whom an alternative diagnosis cannot be established.

  • Always perform a malaria test (thick blood films) in a VHF suspected case and, if not quickly available and/or reliable, start empirical antimalarial treatment.

  • Immediately place the patient in a negative pressure room and alert local infection control unit, state, and national authorities.

  • Health care professionals should always use appropriate barrier and aerosol precautions. Access to patient’s room should be limited to only staff personnel.

  • Supportive therapy is the main stay of treatment, but specific antiviral agent (ribavirin), preferably by intravenous (iv) route, should be started early in the diagnosing setting. Apply easily done diagnostic test (RT-PCR) and discontinue antiviral therapy if the diagnosis of filoviral or flaviviral infection is made.

Introduction

Viral haemorrhagic fevers (VHFs) represent a group of clinically indistinguishable diseases caused by four different families of small, enveloped, RNA virus: Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae.

VHFs poses great medical challenge because:

  • Diseases are associated with a high mortality rate.

  • Many VHFs have the potential for person-to-person transmission (Filoviruses, Arenaviruses, and Bunyaviruses).

  • Widespread international travel made possible for viral agents to migrate from endemic areas to non-endemic areas.

  • Early diagnosis and treatment are paramount for improving clinical outcome and for minimizing health care associated transmission.

Main clinical and laboratory findings, major viral agents, as well as epidemiological characteristics of VHFs are depicted in Table 293.1.

Table 293.1 Main viral haemorrhagic fevers

Disease

Ebola HF

Marburg HF

Lassa HF

HFRS

CCHF

RVF

Severe dengue

Yellow fever

  • Causative virus

  • (Family name)

  • Ebola

  • (Filoviridae)

  • Marburg

  • (Filoviridae)

  • Lassa

  • (Arenadiridae)

  • Hantan

  • (Bunyaviridae)

  • CCHV

  • (Bunyaviridae)

  • RV

  • (Bunyaviridae)

  • Dengue

  • (Flaviviridae)

  • Yellow fever

  • (Flaviviridae)

Distribution

Africa

Africa

West Africa

Eastern Russia, Korea, China, and Balkans

Africa, Middle east, central Asia, Europe

Africa, Saudi Arabia and, subsequently, Yemen

Endemic in Asia, the Pacific, the Americas, Africa, and the Caribbean

Africa and tropical Americas

Transmission

Bat

Bat

Rodent

Rodent

Tick

Mosquito

Mosquito

Mosquito

Human-to-human transmission

Yes

Yes

Yes

Yes

Yes

No

No

No

Incubation (days)

2–21

2–21

7–21

7–21

3–12

2–10

3–10

3–6

Fever

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Haemorrhagic events

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Leucopenia

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Thrombocytopenia

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Liver toxicity

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Prominent

Renal impairment

Yes

Yes

Yes

Prominent

Yes

Yes

Yes

Yes

Mortality rate

High

High

High

High

High

High

High

High

† Other pathogenic members of the Arenadiridae family can also be found in the Americas.

Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine, Geisbert TW and Jahrling PB, 'Exotic Emerging Viral Diseases: Progress and Challenges, 12, S10, pp. S110–21, Copyright © 2004.

VHFs are characterized by acute fever, coagulation disorders and organ specific syndromes such as encephalitis, pneumonitis, nephritis, and arthritis. The severity and clinical presentation of VHFs may vary from an unspecific febrile disease to severe forms with severe bleeding, intravascular coagulation, multiple organ dysfunctions and death. Often, the mechanisms of severe disease include a combination of endothelial dysfunction, causing capillary leak syndrome and bleeding disorders, associated with thrombocytopenia and disseminated intravascular coagulation. Different organ specific syndromes can be more associated to a specific virus family [1,2,3,4,5,6].

In the last years, a substantial progress in the understanding of pathogenesis and dissemination of VHFs has been made. However, to date, lack of available vaccines for most VHFs, absence of potent specific antiviral therapies and the potential for bioterrorism usage of these agents makes VHFs a major global public health concern [7].

Dengue is the most frequent haemorrhagic viral disease and re-emergent infection in the world. Currently, 25–30% of the world’s population lives in areas at risk of dengue infection. It is estimated that there are 50 to 100 million cases of dengue infection per year, and the global incidence of dengue continues to increase. In the last decades a progressive global expansion of the disease including a higher frequency of severe forms (DHF/DSS) was observed. This expansion included tropical and subtropical areas in Americas, Europe, Asia, and Africa. Recently, the burden of dengue was reviewed as more than three times the previously estimated by World Health Organization (WHO). Due to its public health relevance, severe dengue will receive special attention in this chapter.

Pathogenesis

Information regarding the pathogenesis of VHF in humans is limited and, in general, comes from clinical observations and experimental infections in non-human primates (NHP). Careful interpretation of experimental studies is necessary due to virus type, viral load, administration route, host previous immunity, and animal species utilized in these studies.

Endothelial infection is a common finding among the diseases, but can be limited or widespread depending on the agent. In the case of Ebola haemorrhagic fever (EHF) and in severe forms of Rift Valley fever (RVF), the virus has a highly destructive interaction with the endothelium leading to vascular leakage, disseminated intravascular coagulation (DIC), shock, and death. Arenaviruses and dengue, in contrast, infect the endothelium, but these cells are not the primary cellular targets and cause little direct damage to the endothelium; they may induce abnormal cytokine production and disrupt endothelial function, but this is in the absence of obvious morphologic signs. Other viruses, such as Hantaviruses, are virtually non-cytopathic, can infect cells in vitro without inducing any permeability or other major change, and depend on the host immune response to induce changes in vascular permeability [8,9,10].

All VHF induces thrombocytopenia. Different degrees of platelet dysfunction, including platelet activation, apoptosis, elevated clearance, and abnormal thrombopoiesis, are well documented in severe dengue, Ebola, Lassa fever, and Arenavirus infection. Decreased levels of coagulation factors, frequently observed and derived from hepatic failure or DIC, can be observed in yellow fever (YF) and RVF.

High concentrations of pro-inflammatory cytokines (cytokines storm) clearly play an important role in the different VHF infections, but the mechanisms for cytokine induction and their exact role are different and poorly understood among the infections. The clotting defects are also quite variable in both their obvious manifestations and their pathogeneses.

Most of the VHF produce very severe symptoms in their infections; however, dengue virus infections produce distinct disease outcomes. The immunopathological mechanisms responsible for the increased disease severity associated with severe dengue are only partially understood. Several lines of evidence have indicated that non-neutralizing anti-DENV antibodies play a modulatory role that involves antibody-dependent enhancement (ADE) of infection, via Fc-gamma receptor (Fcγ‎R)-facilitated virus entry. However, other factors, including altered T-cell responses, virus strain virulence, and innate immunity have been implicated in modulating the clinical outcome of the infection. These data support four non-mutually exclusive theories to explain the immune mechanisms leading to DHF [2,4,11,12]. The main theories are:

  • ADE: anti-DENV antibodies can form non-neutralizing immune complexes with the virus and facilitate the infection of cells expressing Fcγ‎R.

  • Original antigenic sin (OAS): memory T-cells are abnormally activated by altered peptide epitopes that are capable of production of high levels of cytokines, but are not effective in killing infected cells.

  • Dengue strain virulence (DSV): specific strains of the dengue virus, of any of the serotypes, are more able to replicate in the human host tissues.

  • Host innate responses (HIR): the specific human genetic background influenced by environmental factors can result in inadequate innate responses, notably, dendritic cells, type I and II interferon responses and responses of the complement system.

Clinical presentation and laboratory findings

Describing in details clinical and laboratory findings of each viral agent is beyond the scope of this chapter and has been recently reviewed elsewhere (WHO 2009 and 2013). Major clinical and laboratory features, shared by the four viral families aforementioned (Filoviridae, Arenadiridae, Bunyaviridae, Flaviviridae), are depicted here.

Patients usually become abruptly ill after an incubation period of 3–21 days. At presentation, fever, chills, headache, joint and muscle aches, fatigue, diarrhoea, nausea, vomiting, sore throat, and conjunctivitis can be present. Routine laboratory panel performed at this point should display leukopenia with lymphopenia, thrombocytopenia, and a mild to moderate elevation in liver enzymes (AST and ALT). Leukocytosis can also be observed usually after the second week of symptoms on filoviral infections. Prominent liver involvement is a common feature of YF and, together with patient’s travel history, could help in distinguishing between different VHFs syndromes. Prominent renal impairment is a typical feature of haemorrhagic fever with renal syndrome (HFRS) and, together with a longer incubation period (usually 2 weeks) and patient’s travel history, should point towards this diagnosis. As disease progresses, coagulopathy, with prolonged prothrombin (PT) and partial thromboplastin times (PTT), altered mental status, renal and liver , and DIC becomes evident. Haemorrhagic manifestations can include petechial skin rash, epistaxis, haematemesis, melena, conjunctival and venipuncture site bleeding and, finally, death.

Severe dengue is characterized by clinical and laboratorial evidence of increased capillary permeability and plasma leakage. After the febrile phase, patients experience sudden defervescence, circulatory and perfusion changes (hypotension and hypovolemic shock), ascites and pleural effusion, and organ dysfunctions such as liver failure, encephalitis, myocarditis, and clotting disorders. Usually a sudden drop of leucocytes and platelets precedes plasma leakage, and a progressive haematocrit increase can be observed reflecting the magnitude of haemoconcentration. The critical phase, which is evident in 10–15% of dengue cases, discloses the progression to severe disease. The duration of this phase is 1–3 days.

Differentials

Most important differentials are depicted in Table 293.2.

Table 293.2 Relevant differentials for VHFs

Bacterial and rickettsial infections

Viral and parasitic infections

Non-infectious conditions

  • Leptospirosis

  • Meningococcaemia

  • Gram-negative bacterial septicaemia

  • Typhoid fever

  • Rocky Mountain spotted fever

  • Malaria

  • African trypanosomiasis

  • Viral hepatitis

  • Thrombotic or idiopathic thrombocytopenic purpura

  • Haemolytic uraemic syndrome

Diagnosis

Diagnosis should be considered in a sick traveller from an endemic area in whom an alternative diagnosis cannot be made (see Table 293.2 for relevant differential diagnosis). Malaria test (thick blood films) should always be performed in a suspected VHF case and, if not quickly available and/or reliable, empirical antimalarial treatment should be initiated. Lack of clinical and laboratory response to antimalarials and/or to the treatment of most common bacterial infections should raise suspicion of VHF in a patient returning from an endemic area. It is likely that most VHF suspected cases will end up with a more common definitive diagnosis; nevertheless, early diagnosis is paramount for achieving a better clinical outcome.

Specific diagnoses of VHFs agents are usually obtained on blood samples by detecting specific antibodies, viral antigens (ELISA), viral nucleic acid (reverse transcriptase polymerase chain reaction (RT-PCR)) and virus isolation.

Detection of specific IgM antibodies or a four-fold increase in IgG antibody titres can be achieved by collecting acute-phase blood samples within 7 days of illness and convalescent-phase blood samples 8–20 days later. Detection of antibodies can be difficult because they are not easily detected early in the course of the diseases and some patients, usually associated with fatal outcome, fails to produce robust immune response. RT-PCR is an important diagnostic tool and offers the advantage of rapid detection with high sensitivity and specificity even in the first days of illness, when antibody titres are still low. Viral nucleic acid detected by RT-PCR can be performed even a few days after the viraemic period. Virus isolation should only be performed in laboratories biosafety level 3 or above.

Dengue infection can be firmed by detecting viral antigen (Ns1Ag), virus isolation, or RNA virus detection (RT-PCR). Around the fifth day, viremia and antigenemia disappear, which coincides with the appearance of specific antibodies. From the sixth day, IgM ELISA is the method of choice for diagnosis of dengue. High levels of IgM and low levels of IgG characterize primary infections, while low levels of IgM with high levels of IgG suggest secondary infections. In dengue endemic countries, acute clinical cases with a positive IgM are classified as probable dengue cases. The study of paired sera (acute and convalescent serum samples with the second sample being collected 15–21 days after the first sample), allows for serological confirmation of dengue infection.

Treatment in the intensive care setting

VHFs greatly resembles sepsis pathogenesis and their approach in the intensive care setting is quite similar. Intravenous volume replenishment, management of pain, anxiety and electrolyte imbalance is essential. Aggressive treatment of multi organ dysfunctions and haemorrhagic events frequently requires vasoactive drugs, haemodialysis, mechanical ventilation, platelet transfusion, and red blood cells transfusion.

Adjunctive antimicrobial therapy is usually implemented to treat coexisting or secondary infections. Antimalarial treatment should also be initiated if a malaria test (thick blood films) is not quickly available and/or reliable, and patients travel history is compatible.

Empirical antiviral treatment with Ribavirin should be started as soon as a case of VHF is suspected. Ribavirin (1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) interfere with intracellular RNA and DNA synthesis and subsequently inhibits protein synthesis and viral replication of ribavirin-sensitive RNA or DNA viruses. Ribavirin should be preferably administered through iv route. Start with a loading dose of 30 mg/kg, followed by 16 mg/kg every 6 hours for 4 days, followed by 8 mg/kg every 8 hours for 5–10 days (Ribavirin treatment should be maintained if Arenavirus or Banyavirus infection). Ribavirin comes in vials of 1000 mg and 800 mg, to be diluted in 10 mL phosphate buffer solution. Infuse over 10–15 minutes. Major side effects and caution includes haemolytic anaemia, pancytopenia, pancreatitis, renal, and liver impairment.

The cornerstone for severe dengue therapy is a rapid recovery of the effective volaemia through an adequate fluid resuscitation (recently reviewed by WHO experts [6]‌). Briefly, a reference haematocrit (Ht) obtained before to start the fluid therapy, associated with the BP, will be major parameters to be used to evaluate the response to the therapy. To patients with shock, start iv fluid resuscitation with isotonic crystalloid solutions at 20 mL/kg as a bolus given over 15–30 minutes. If the patient’s condition improves maintain the infusion at 10 mL/kg/hour for 1 hour more. Then gradually reduce to 5–7 mL/kg/hour for 1–2 hours, then to 3–5 mL/kg/h our for 2–4 hours, and finally to 2–3 mL/kg/hour (or less), which can be maintained for up to 24–48 hours.

When hypoperfusion signs persist after volume infusion in association with a drop in Ht it should be suspect bleeding complications. Red blood cell transfusion is indicted if there is severe overt bleeding, and transfusion of platelet concentrate is indicated for patients with lower than 50,000/mm3 platelets with suspected severe bleeding.

If the Ht increases compared to the reference Ht or remains high continue fluid infusion at 10–20 mL/kg as a third bolus over 1 hour, colloid solution can be used. After this dose, reduce the rate to 7–10 mL/kg/hour for 1–2 hours, and then reduce the rate of infusion as mentioned previously when the patient’s condition improves [15,16,17,18].

Biosafety measures

Installation of proper biosafety measures should not be delayed by any laboratory test. Notify local infection control unit and state and national authorities. All suspected cases of VHF should be immediately placed in a negative pressure room and access should be limited to necessary only staff personnel. Face shields, goggles, N-95 masks or powered air-purifying respirators, double gloves, impermeable gowns, leg, and shoe coverings should be worn while handling the patient. After handling the patient, it is mandatory to remove and discard gown, leg and shoe coverings, and gloves. Proper hand hygiene should be performed prior to the removal of facial protective equipment to minimize exposure of mucous membranes. Patient care equipment including thermometers, blood pressure cuffs and stethoscopes should be dedicated to the patient. If patient dies, handling of the body should be minimal.

Acknowledgements

The authors would like to acknowledge Ernesto Marques whose help in writing this chapter was greatly received.

References

1. Geisbert TW, Jahrling PB. (2004). Exotic emerging viral diseases: progress and challenges. National Medicine, 10, S110–21.Find this resource:

2. Kortepeter MG, Bausch DG, Bray M. (2011). Basic Clinical and Laboratory Features of Filoviral Hemorrhagic Fever. Journal of Infectious, 204(3), S810–6.Find this resource:

3. Meltzer E. (2012). Arboviruses and Viral Hemorrhagic Fevers (VHF). Infectious Disease Clinic North America, 26(2), 479–96.Find this resource:

4. Paessler S, Walker DH. (2013). Pathogenesis of the Viral Hemorrhagic Fevers. Annual Review of Pathology: Mechanisms of Disease, 8(1), 411–40.Find this resource:

5. Peters CJ, Zaki SR. (2002). Role of the endothelium in viral hemorrhagic fevers. Critical Care Medicine, 30(5), S268–73.Find this resource:

6. Kunz S. (2009). The role of the vascular endothelium in arenavirus haemorrhagic fevers. Journal of Thrombosis and Haemostasis, [Internet.] Available from: http://www.schattauer.de/index.php?id=1214&doi=10.1160/TH09-06-0357 (accessed 22 April 2013)

7. Borio L, Inglesby T, Peters CJ, et al. (2002). Hemorrhagic fever viruses as biological weapons: medical and public health management. Journal of the American Medical Association, 287(18), 2391–405.Find this resource:

8. Morens DM, Fauci AS. (2008). Dengue and hemorrhagic fever. Journal of the American Medical Association, 299(2), 214–6.Find this resource:

9. Simmons CP, Farrar JJ, Nguyen van VC, Wills B. (2012). Dengue. New England Journal of Medicine, 366(15), 1423–32.Find this resource:

10. Bhatt S, Gething PW, Brady OJ, et al. (2013). The global distribution and burden of dengue. Nature, 496(7446), 504–7.Find this resource:

11. Towner JS, Khristova ML, Sealy TK, et al. (2003). Marburgvirus Genomics and Association with a Large Hemorrhagic Fever Outbreak in Angola. Journal of Virology, 80(13), 6497–516.Find this resource:

12. Yun NE, Walker DH. (2012). Pathogenesis of Lassa fever. Viruses, 4(10), 2031–48.Find this resource:

13. Special Programme for Research and Training in Tropical Diseases, World Health Organization, World Health Organization. (2009). Epidemic and Pandemic Alert and Response. Dengue guidelines for diagnosis, treatment, prevention, and control. Geneva: WHO [Internet.] Available from: http://site.ebrary.com/id/10363988 (accessed 15 April 2013).

14. World Health Organization (2015). Handbook for Clinical Management of Dengue. Geneva: WHO [Internet.] Available from: http://www.who.int/denguecontrol/9789241504713/en/ (accessed 8 December 2015).

15. Handy JM. (2004).Viral haemorrhagic fevers—implications in intensive care. Current Anaesthesia & Critical Care, 15(3), 137–42.Find this resource:

16. Roddy P, Colebunders R, Jeffs B, Palma PP, Van Herp M, and Borchert M. (2011). Filovirus hemorrhagic fever outbreak case management: a review of current and future treatment options. Journal of Infectious Diseases, 204(3), S791–5.Find this resource:

17. Marra A, de Matos G, Janeri R, et al. (2011). Managing patients with dengue fever during an epidemic: the importance of a hydration tent and of a multidisciplinary approach. BMC Research Notes, 4(1), 335.Find this resource:

18. Hung NT. (2012). Fluid management for dengue in children. Paediatrics and International Child Health, 32(1), 39–42.Find this resource: