Monday, 11 August 2008

A Case of Fever and Headache- The Answer

Dear Bloggers

Below are the answers to the recently published case.


1) Bearing in mind the history, physical examination, and basic laboratory data, please make a problem list.

  • Recent Travel to Thailand
  • Insect bite (s)
  • Fever
  • Headache
  • Chills
  • Malaise
  • Generalised Arthralgia and Myalgia
  • Weight loss
  • Retro-orbital pain
  • Mild petechial rash
  • Mild splenomegaly
  • Mild muscle pain
  • Neutropenia and mild thrombocytopenia
  • Elevated CK, AST and LDH

2) Taking into account the geographic location please list the possible differential diagnoses that could result in the above features.

This history is consistent with an infective aetiology although other causes should also be considered such as drug induced, connective tissue disease, neoplastic, and haematologic diseases.

Infective causes
from this area of the world include:
  • Malaria
  • Dengue (haemorrhagic) fever
  • Leptospirosis
  • HIV
  • Typhoid fever
  • Scrub Typhus
  • Rickettsia
However, other infective causes that could result in similar features include:
  • Parvovirus B19
  • Infectious mononucleosis
  • Cytomegalovirus
  • Hep A, B, C
  • Infective Endocarditis
However, the fact that the patient received an insect bite it is mostly likely to be a mosquito and hence, mosquito-blood-borne diseases should be highly suspected. The history is very important here. The patient did not go through jungle areas on foot and this makes tick bites unlikely and with no exposure to contaminated water e.g. swimming in rivers, also makes Leptospirosis less likely. The fact that a sexual history was not obtained is a pity as there is a high level of HIV in Thailand and the above features could be consistent with an acute HIV seroconversion illness. Being of advancing age does not preclude sexual intercourse and a sexual history should be taken when appropriate.

Drug-induced causes:
This patient takes Lansoprazole and Allopurinol. Both drugs can affect the bone marrow resulting in blood dyscrasias. Always consider drugs as an actual cause or a contributory cause and if in doubt the drugs should be discontinued either temporarily or permanently.

Connective Tissue Disease (CTD):
This problem should be considered although I do not think it is very likely. Vasculitis can present with headaches, fever, weight loss, arthralgia, myalgia, petechial bleeding, splenomegaly etc. Even the neutropaenia and thrombocytopaenia could be accounted for by a CTD. Such examples might include SLE, Adult Still's disease, Rheumatoid vasculitis and Temporal arteritis with PMR [blood dyscrasias as outlined above are not consistent with this diagnosis].

Adult Still's disease usually presents in adolescents and young adults although it has been described in older patients and has a bimodal age distribution. It is a cause of the haemophagocytic syndrome. It is very unlikely in this case.

Rheumatoid vasculitis usually presents after many years of chronic RA and hence, in the absence of this history, it makes such a diagnosis very unlikely.

Neoplastic: The fact that this patient had a previous tumour is important. One would want to know the previous Duke's staging to consider whether metastatic disease was a possibility. However, in view of the abrupt onset and history of foreign travel, the consideration of malignancy as the cause is very unlikely here.

Haematologic: Other haematological disease that could account in part for the symptoms include the acute leukaemias with secondary infection from neutropaenia. Lymphoma with autoantibody production against neutrophils and platelets is a possibility too although again, as I have mentioned, with the history of travel and abrupt onset of symptoms, it would seem that a primary haematological cause is less likely.

3) What tests need to be done?

In this case an infective aetiology is likely. Tests should include:
  • Thick and Thin Blood Smears to investigate Malaria. The Thick film of blood is used to make the diagnosis of malaria and is positive on the first smear in 95% of cases. However, they should be repeated every 6-12 hours if initially negative for up to 48 hours to rule out this infection. The Thin films are used to determine the malaria spp and the extent of parasitic load in the blood.
  • Falciparum antigen testing / HRP-2 / parasite LDH / PCR (if available)
  • Antibody / Antigen / PCR testing for Dengue, Typhus, Rickettsia, Leptospirosis, HIV (if there is a high risk history), EBV, CMV, Parvovirus B19, Hepatitis A, B, C
  • Blood cultures x 3 and cardiac echo- infective endocarditis can present as a 'vascilitis' and the murmur may not initially be appreciated.
  • Urine analysis and culture to exclude infection
  • Stool culture e.g. salmonella
Other tests to consider include:
  • Checking the blood smear for a primary blood dyscrasia
  • Bone Marrow Examination
  • Autoimmune profile plus anti-platelet antibodies

4) What is the likeliest diagnosis in this patient?

In view of the recent history of travel to Thailand, a mosqito bite and the various symptoms including retro-orbital pain and a mild petechial rash, in addition to the neutropenia and thrombocytopaenia, the dengue haemorrhagic fever should be considered highly likely.

However, the other above cited differential diagnoses need to be considered and appropriately investigated and excluded because the respective treatments are different.

For example, scrub typhus is due to infection from Orientia tsutsugamushi which is similar to but also distinct from usual Rickettsial spp. It can also produce retro-orbital pain, myalgia and a rash (sometimes petechial). It has been described for such infections to be transmitted in suburban Bankok.

Leptospirosis is a predominatly water borne infection and has classically been caused from exposure to water contaminated with leptospira from infected rats urine. The organism usually gains entry from an abrasion in the skin and causes similar features as in this case. However, one usually develops a leukocytosis rather than a leukopaenia which goes some way against this being the cause. However, 90% of leptospira infections are self-limiting (not Weil's disease) and the organisms are cleared within a week. Hence, this diagnosis would need to be ruled out.

Malaria is one of those diagnoses that should always be investigated and ruled out. This patient did not use malaria prophylaxis putting her at potential risk for malaria infection. Malaria can present similarly to the above patient and hence, doing the appropriate exclusion tests is a necessity.

The current guidance for tourists going to Thailand as per UpToDate 16.2 suggest that urban transmission and daytime rural exposure to malaria are very low and that prophylaxis is not necessary. One needs to however avoid insect bites [this patient did not avoid such bites!]

However, if there is going to be potential exposure e.g. travel to rural areas with exposure during the evenings (when mosquitos are most active) then prophylaxis is recommended. There is a high level of chloroquin, mefloquin and Fansidar resistance in Thailand and hence, prophylactic regimens should include doxicycline or Malarone prophylaxis.

Hence, a patient with a history of possible exposure to malaria e.g. mosquito bite with the above symptoms e.g. fever, headache etc, should have malaria excluded. Please see the detailed UK guidance on the following link

5) What is the treatment?

For Dengue (haemorrhagic) fever of this severity, the patient was isolated in a positive pressure room. The malaria screen was negative. Several of the above tests could not be investigated e.g. the test for Dengue was not available, although the bone marrow examination excluded a leukaemia / lymphoma and an autoimmune profile was within normal limits.

The patient was considered to have a virally induced haemophagocytic syndrome which was seem on the bone marrow examination and she was started on high dose steroids and immune globulin infusions.
The above therapy is not usually necessary for treatment of typical uncomplicated Dengue as it is usually self-limiting and supportive treatment is the norm. Before starting high dose steroids in such a patient, one should always try to rule out other serious infectious aetiologies first e.g. TB.

There have only been a handful of cases of the reactive haemophagocytic syndrome being described in Dengue Fever [
medline - hemophagocytic & dengue as search criteria] and such an occurrence appears to be unusual.

Reviewing the latest UpToDate 16.2, for such a reactive viral aetiology, treating the underlying cause is the first measure (if of course there is a treatment available) and failing that, it is advocated to start Dexamethasone plus Cyclosporin. However, there have been case reports of intravenous immunoglobulins showing some effect. High dose steroids are usually of limited benefit.

The causes and pathophysiology of the Viral Haemophagocytic Syndrome is complex and I would refer you to a more detailed text such as UpToDate.

Dr Stein, University of Florida, has kindly provided his answers to the case below:

1. Problem list
  • Fever
  • HA/retro-orbital pain
  • Chills
  • Malaise
  • arthralgias/myalgias
  • foreign travel
  • weight loss
  • drug adverse reaction potential
  • petichial rash
  • splenomegaly
  • leukopenia
  • borderline thrombocytopenia
  • elevated CK, AST

2. a. Viral infection: adenovirus, coxsackie, enterovirus, dengue, HBV, EBV, parvovirus B19, HIV, typhoid fever, rickettsia, malaria, chikungunya- were RBC's in urine? where is U/A?

2b Allopurinol hypersentivity syndrome

3. Viral Ab tests, Salmonella, shigella Ab/blood cultures, wet blood smears

4. Dengue fever

5. Supportive

Many thanks to Dr Stein for the concise answers to the questions.

In the end, this patient made a superb recovery over a 5-day period. The neutrophil and platelet counts recovered and the patient's symptoms dissipated. Whether the recovery of the blood abnormality was as a result of the therapy or the natural course of the viral illness is not certain.