Dengue fever is mentioned in Sivakumar and Pelly's chapter on tropical diseases in Oh's Manual.

Given the recent excitement associated with the return of Ebola-infected health care workers into the developed world, wealthy white Anglo-Saxon ICU specialists have suddenly developed a renewed interest in viral haemorrhagic fever. As a "trending topic", it may appear as an SAQ (H1N1 influenza certainly fit the same description, and was favoured with an appearance among the SAQs).

This summary will focus on Dengue (as it is in The Manual, is represented among Australian returning travellers and Northern Australian residents, and therefore makes sense as a study topic) and on Ebola (as it was the hot new thing, at the time of writing in early 2015). Indeed, shortly after this chapter was written, in Question 22 from the second paper of 2015 Ebola did in fact make an appearance.

Ideal non-Oh's sources for this topic can be listed for the person who refuses to own Oh's.

Virology of viral haemorrhagic fevers

The list of VHFs includes:

  • Dengue
  • Ebola
  • Crimean-Congo fever
  • Rift Valley fever
  • Lassa
  • Marburg virus
  • Yellow fever

Members belong to families of filoviruses, flaviviruses, arenaviruses and bunyaviruses.

Typically, there is an animal reservoir (eg. the Aedes mosquito for Dengue) and the history involves some exposure to it.

Dengue haemorrhagic fever:

  • Infection with one of the four serotypes provides life-long immunity against that serotype, but not against the other serotypes.
  • Incubation period of 3–14 days
  • Sudden onset of symptoms:
    • Fever
    • Severe headache
    • Retro-orbital pain on moving the eyes,
    • Severe fatigue
    • Maculopapular rash
    • Injected conjunctiva
    • Pleural effusion
    • Ascites
    • Bleeding
    • Severe myalgia (especially the back muscles)
    • Profound hypotension and shock
    • A positive tourniquet test - the rapid eruption of petechii upon application of a tourniquet to the limb ( a part of the WHO diagnostic algorithm)

Laboratory Features of Dengue Haemorrhagic Fever:

  • Haemoconcentration (20% rise in haematocrit) - "plasma leakage"
  • Thrombocytopenia
  • Leukopenia
  • Raised AST

Confirmation of diagnosis

  • IgM serology (may need a convalescent sample
  • Viral nucleic acid detection by reverse transcriptase PCR

Management of the plasma leakage syndrome

This issue is complicated by the persistent need to fill a compartment in which the fluid simply refuses to stay. Fortunately, this "leaky phase" only lasts about 48 hours.

The WHO recommends a strategy of fluid resuscitation, which can be summarised as "fill them with crystalloid and don't stop for anything". The endpoint seems to be the normalisation of the rising haematocrit. Albumin is probably also permitted.

Ebola virus

Virology

  • a filovirus; five species have been identified: Taï Forest (formerly Ivory Coast), Sudan, Zaire, Reston and Bundibugyo.
  • Each virion contains one molecule of single-stranded, negative-sense RNA.
  • Ebola is a zoonosis: the natural host is a group of fruit bats from the Pteropodidae family.
  • From these bats, numerous species of local animals become infected (presumably, the bats shed the virus in various secretions, which spray copiusly upon the heads of other jungle fauna).
  • Contact with infected animals produces human vectors.
  • Infection occurs through contact of infected body fluids with mucosal surfaces or skin or through parenteral injection. It is not aerosolised.
  • The virus disseminates to the lymph nodes, liver, and spleen.
  • There is little initial inflammatory response and significant lymphocyte apoptosis.
  • Inhibition of the type I interferon response seems to be important in the pathogenesis.
  • Ultimately, macrophage overactivation and clotting cascade dysregulation result in the shock state and organ system damage.

Clinical features

There is an excellent article by Kortepeter (2011) which covers this topic well.
In brief summary:

  • Returning traveller
  • Incubation period of 2-21 days
  • Death typically occurs between day 6 and 16 with hypovolaemic shock and multiorgan failure. Again, as with Dengue (and with all these haemorrhagic fevers) the main issue seems to be increased vascular permeability.
  • On autopsy,  the principal gross abnormality is the presence of multiple foci of hemorrhage. 
Clinical Features of Progressing Ebola Infection

Initial Stage

Intermediate stage

Advanced stage

Initially, the features are non-specific
  • Fever, chills (87%)
  • Malaise, loss of appetite (63%)
  • Myalgia (39%)
  • Arthralgia (39%)
  • Dissociation of fever and tachycardia (i.e. the febrile Ebola patient will be bradycardic)

A flu-like illness then develops:

  • Fatigue, prostration (76%)
  • Nausea, vomiting (68%)
  • Abdominal pain (44%)
  • Diarrhoea (66%)
  • Shortness of breath, cough
  • Headache (53%)

Haemorrhagic symptoms follow:

  • Conjunctival injection
  • Petechii, ecchymoses
  • Macropapular rash
Organ system failure progresses:
  • Renal failure
  • Hepatic dysfunction
  • Consumption coagulopathy
  • "Plasma leakage" syndrome
  • Obtundation and coma
  •  
  • ARDS

Laboratory findings

This excellent 2014 article contains a table which lists many of these findings.

  • Early leukopenia and lymphopenia
  • Thrombocytopenia
  • High AST and ALT
  • Hypoalbuminaemia (in contrast to the haemoconcentration of Dengue)
  • Hypionatremia
  • Hypokalemia
  • Hypocalcemia
  • Lactic acidosis
  • Coagulopathy with low fibrinogen and high D-dimers (DIC)
  • Some degree of renal impairment

Diagnostic tests

  • IgG and IgM ELISA and antigen RT-PCR are the gold standard.
  • Viral antigen and nucleic acid can be detected in blood from day 3 up to 7–16 days after onset of symptoms.
  • Typically, a specialised lab is ging to be involved, and results are going to be delayed

Management

  • Well, its supportive.
  • Tellingly, many of the management guidelines conclude with detailed instructions for safe and dignified burial practices.
  • Some experimental-sounding treatment strategies are listed in the Lancet article:
    • Activated protein C (good luck getting hold of it)
    • Survivor serum (antibodies from convalescent survivors)
    • Type I interferons
    • Ribavirin
    • Nematode-derived anticoagulation protein rNAPc2

Public health and infection control issues

The college may present the candidates with a confirmed case (or a rapid proliferation of cases). In Question 22 from the second paper of 2015 they dwelled extensively on the issues of isolation and staff safety.

In this fashion, one might answer the questions "discuss your management" or "discuss your considerations in developing a preparedness plan for such an outbreak".

Administrative and logistic considerations

  • Staff training for VHF personal protective equipment (PPE).
  • Specific instructions to transport and retrieval staff trained in VHF PPE.
  • Specific plans regarding transfer of confirmed cases to a dedicated facility.
  • Dedication of a specific "VHF designated" facility, where specialist staff are concentrated.
  • Need for dedicated isolation rooms, with specific features.
Viral haemorrhagic Fever Infection Control Measures

Specific personal protective equipment

Specific features of the patient room

  • Surgical scrubs (not your comfy home clothes)
  • Disposable long sleeve gown
  • Face shield
  • Surgical hood
  • P2/N95 mask or disposable powered air purifying respirator (PAPR) hood
  • Fluid repellent below-knee boot covers
  • Double gloves with long cuffs
  • Single room with door closed
  • Ideally, a negative pressure room
  • Own bathroom; not connected to central sewer (special disposal arrangements)
  • Strict limits on visitors (none!)
  • Special arrangements for disposal of patient's wastes and disposable equipment

The NSW Health Ebola document is publically available, and is detailed to an absurd level of granularity: "Should an isolated patient require delivery of a meal tray all equipment provided (e.g. utensils, plates and containers) must be disposable, including the tray. If disposable trays are not available, trays must not be taken into the patient room. "

 

Intensive care management of viral haemorrhagic fever

The best resource for this is a 2014 article by West and von Saint Andre-von Arnim. Unlike other papers of this nature, it focuses on the care of the critically ill VHF patient, and goes through it according to the organ systems. Unless otherwise stated, the

Airway

  • Intubation may be required in case of significant respiratory failure.
  • Specific problems may arise:
    • Greatest risk of aerosol transmission will be to the airway operator, who would need to be appropriately protected
    • Coagulopathy could create a post-intubation haemoptysis problem due to relatively trivial airway trauma
    • Frequent suctioning could cause enough airway trauma to produce lower airway haemorrhage

 

Respiratory support

  • Copious volumes of fluid resuscitation may produce pulmonary oedema
  • NIV may be sufficient initially, but has a greater potential to aerosolize secretions.
  • Invasive ventilation is the preferred method.
  • The invasively ventilated patient should be ventilated with lung-protective ventilation.
  • Expired gas from the patient should pass through a HEPA or equivalent filter.
  • Extracorporeal life support is not advised (expecting haemorrhagic complications)

 

Circulatory support

  • Aggressive volume repletion with isotonic fluids
  • Ebola can be complicated by adrenal necrosis; "stress dose" steroids should be considered early
  • Standard noradrenaline is probably going to play a role.

Neurological dysfunction

  • These patients may be obtunded for a variety of reasons.
  • Of the reasons one needs to exclude, the most important are:
    • Intracranial haemorrhage in the coagulopathic patient
    • Seizures (including non-convulsive status)
  • If not obtunded, they may be in pain, feeling isolated, and frightened beyond belief.
  • The authors of the abovelinked study recommend videoconferencing facilities be made available to permit contact with loved ones (a brilliant solution from the infection control perspective, and one which results in the fiery destruction of a contaminated laptop).

Electrolyte abnormalities

  • Massive fluid and electrolyte loss is to be expected
  • Apart from anticipiating and correcting it, no specific recommendations can be made

Fluid balance and renal failure

  • Vast volumes of crystalloid may be used; so you better use a balanced solution.
  • ATN is present on post-mortem of Ebola victims, and is thought to originate from the shock state- correcting the haemodynamic derangement is therefore a priority.
  • Standard indications for renal replacement therapy apply.
  • All effluent must be disposed of in some sort of formalised fashion (like the rest of the Ebola patient material, one cannot simply put it in the routine medical waste bins)

Nutrition

  • If this is a person originating from the characteristic part of Africa where Ebola is endemic, premorbid malnutrition needs to be considered.
  • Thus, refeeding syndrome needs to be watched for
  • No specific recommendations can be made other than to watch for haemorrhagic complications of NGT insertion

Specific therapies

  • To date, none are exactly evidence-based.
  • The cited article lists several experimental therapies, which one shoudl have some passing familiarity with:
    • Brincidofivir (in vitro activity)
    • ZMapp monoclonal antibody cocktail
    • TKM-Ebola i an interfering RNA molecule used to block expression of two viral replication genes
    • Convalescent whole blood
  • Many of these therapies have been approved by the American FDA only because of the ongoing emergency situation. Some are barely in Phase I trials.

References

Chapter 73  (pp. 743) Tropical  diseases  by Ramachandran  Sivakumar  and  Michael  E  Pelly

Pigott, David C. "Hemorrhagic fever viruses." Critical care clinics 21.4 (2005): 765-783.

World Health Organization, et al. Dengue: guidelines for diagnosis, treatment, prevention and control. World Health Organization, 2009.

Soni, Arun, et al. "Management of dengue fever in ICU." The Indian Journal of Pediatrics 68.11 (2001): 1051-1055.

Feldmann, Heinz, and Thomas W. Geisbert. "Ebola haemorrhagic fever." The Lancet 377.9768 (2011): 849-862.

Paessler, Slobodan, and David H. Walker. "Pathogenesis of the viral hemorrhagic fevers." Annual Review of Pathology: Mechanisms of Disease 8 (2013): 411-440.

del Rio, Carlos, et al. "Ebola Hemorrhagic Fever in 2014: the tale of an evolving epidemic." Annals of internal medicine 161.10 (2014): 746-748.

Fowler, Robert A., et al. "Caring for critically ill patients with Ebola virus disease. Perspectives from West Africa." American journal of respiratory and critical care medicine 190.7 (2014): 733-737.

West, T. Eoin, and Amélie von Saint André-von Arnim. "Clinical Presentation and Management of Severe Ebola Virus Disease." Annals of the American Thoracic Society 11.9 (2014): 1341-1350.