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Typhoid fever

Pathogen:Bacteria →Gram-negative rods →Salmonella enterica serotype Typhi
Transmission:Faecal-oral, for example through contaminated food
Geographical range:Worldwide; most prevalent in areas with poor sanitation
Incidence:21 million infections per year

Case history

A 35-year old man living in Indonesia had been suffering from a high fever for four days. He also had the following symptoms: shortness of breath, headache, poor appetite, vomiting, abdominal pain and pain in his major joints. On day four he visited his general practitioner. Based on the patient’s symptoms and clinical signs, the physician suspected that the man could be suffering from some form of infectious disease (possibly malaria, typhoid fever or pneumonia) and as a first step in the differential diagnostic process he decided to order a complete blood count to investigate the cause of his persistent symptoms.

Typhoid fever pathophysiology and diagnostics

Typhoid fever (TF) is an intracellular bacterial infection caused by gram-negative rod Salmonella enterica subsp. enterica serotype Typhi (S. typhi). Each year there are some 21 million reported infections and around 200,000 deaths. The disease mostly affects children and young adults and is currently most common in India, Southeast Asia and sub-Saharan Africa. In the developed world, the prevalence of the disease decreased in the middle of last century, mostly as a result of improved sanitation and better treatment options due to antibiotics. However, S. typhi is rapidly developing resistance against antibiotics in Africa, where the number of infections is rising and resistance to older antibiotics is growing significantly.

The bacteria spreads through poor hygiene habits and public sanitation conditions. TF does not affect animals and only spreads in environments where human faeces or urine come into contact with food or drinking water. Industrialisation, and in particular the invention of the car contributed to the elimination of typhoid fever, as they eliminated the health hazards associated with horse manure in the streets, which led large numbers of pathogen-transmitting flies (1).

S. typhi enter the host primarily through the distal ileum. They adhere through specialized fimbriae that attach to the epithelium over clusters of lymphoid tissue (Peyer patches) in the ileum. Macrophages recognise pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides, which triggers toll-like receptors TLR-5 and TLR-4, respectively. Macrophages, dendritic and intestinal epithelial cells then attract T-cells and neutrophils, causing inflammation (2,3). S. typhi has a capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation to a large extent. This may explain the greater infectivity of S. typhi compared with paratyphi serovar.

S. typhi is an intracellular bacterium and needs the macrophages’ cellular machinery for its own reproduction, as they are carried through the mesenteric lymph nodes to the lymphatics and then to the reticuloendothelial tissues of the liver, spleen, bone marrow and lymph nodes. Once there they continue to multiply until a critical mass is reached. Then S. typhi induces macrophage apoptosis and breaks out into the bloodstream to invade the rest of the body (3).

Once they have entered the bloodstream, the bacteria infect the gallbladder and the bile. The result is that the pathogen again enters the gastrointestinal tract in the bile and re-infects Peyer patches. Bacteria that do not re-infect the host are typically shed in the stool and are then available to infect other hosts.

Typhoid fever is a systemic form of salmonellosis, where S. typhi enter the lymphatic system. Endotoxins released from the bacterial cell wall act on the vascular system and result in an increased permeability and decreased vascular tone. In severe forms of the disease, liquid and electrolytes are lost to compensate for the water-salt metabolism. The decreased circulating blood volume and arterial pressure can cause haemorrhagic shock and in some cases septic shock may also develop.

The physician usually suspects typhoid fever based on patient’s symptoms, medical and travel history. The final diagnosis is commonly made by identifying S. typhi in a blood, bone marrow or stool culture and with the Widal test (demonstration of antibodies against S. typhi O-somatic and H-flagellar antigens). The Widal serological test is time-consuming (7-14 days) with a limited applicability in early diagnosis. Often, by the time a diagnosis is made, it is too late to start antibiotic treatment. Thus in less wealthy countries during  epidemics - after excluding malaria, dysentery or pneumonia - a therapeutic trial phase with chloramphenicol is generally undertaken while awaiting the results of the Widal test and blood and stool cultures (4).

Typhidot is another diagnostic test based on the ELISA kit that detects IgM and IgG antibodies against the outer membrane protein of the S. typhi. The typhidot test becomes positive within 2-3 days and IgM shows recent infection, whereas IgG signifies older infection. The test is only qualitative.

Laboratory results

 

Case interpretation

The XN results revealed moderate thrombocytopenia and normal RBC and WBC counts. However, the WDF channel detected an activation of three WBC cell lines (neutrophils, monocytes and lymphocytes) with a dominant neutrophil population (NEUT% = 81.3%). The ratio between the neutrophil and lymphocyte counts was increased (NEUT#/LYMPH# = 6) and total lymphocytes were only 13.4% of WBC. Beside the activated neutrophil population shown by the increased value of NEUT-RI parameter (=59.2 FI), only 3.8% reactive lymphocytes (RE-LYMP%) of all leucocytes showed activation. This is 28% of all lymphocytes. Total monocytes are 5% of WBC and 50% of the monocytes showed an increased fluorescence intensity.

This immunological cell reaction profile (no increase in absolute WBC count, but dominant neutrophil population and activation of all three cell lines) is indicative of an early immune reaction possibly to an intracellularly located bacterial pathogen. As described in the pathophysiology and diagnosis section, S. typhi has masked PAMPs on the cell wall and thus avoids stronger neutrophil-based inflammation typical for high innate immune response to extracellular bacterial infection (generally characterised by neutrophilia, left shift and immature granulocytes). The increased neutrophil/lymphocyte ratio and normal to low total lymphocyte count (relative lymphocytopenia) could also probably exclude viral pathogen as a possible cause of this patient’s infection.

The PLT count originating from the PLT-F channel was low (59 x 109/L) and a moderately increased relative immature platelet fraction (IPF, 11.8%) without a high absolute immature platelet count suggested chronic disseminated intravascular coagulation (cDIC).  cDIC reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of platelet tissue factor. Compensatory mechanisms in the liver and bone marrow are not overwhelmed, and there may be little obvious clinical or laboratory indication of the presence of DIC.

The RET channel showed a pathology in erythropoiesis represented by a decreased RET count and negative Delta-He value. This also indicates an acute bacterial infection due to iron sequestration in the macrophages.

The overall blood count results are indicative of an early stage intracellular bacterial infection, although non-specific for S. typhi infection. In the end, the TF infection has to be diagnosed by more specific laboratory tests. In this case three days after the described blood results the presumed diagnosis of typhoid fever was confirmed by positive typhidot IgM test.

References

  1. World Health Organization (2003): The diagnosis, treatment and prevention of typhoid fever
    http://www.who.int/rpc/TFGuideWHO.pdf
  2. Raffatellu M, Chessa D, Wilson RP, Tükel C, Akçelik M, Bäumler AJ (2006): Capsule-mediated immune evasion: a new hypothesis explaining aspects of typhoid fever pathogenesis. Infect Immun. Jan;74(1):19-27
  3. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ (2002): Typhoid fever. N Engl J Med. Nov 28;347(22):1770-82.
  4. Ryan KJ, Ray CG (2004): Sherris Medical Microbiology (4th ed.). McGraw Hill.  ISBN 0-8385-8529-9.

Advanced clinical parameters

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