Fever, Abdominal pain, Constipation and Mary

Gram negative bacilli infections include:

• Escherichia coli
• Nontyphoidal Salmonella
• Salmonella typhi and paratyphi
• Shigella
• Campylobacter
• Vibrio cholerae
• Klebsiella

Based on his symptoms, in particular the lack of diarrhoea, plus his travel history the most likely infective agent is Salmonella Typhi.

Although typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania, the great majority of cases come from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or Vietnam.

Typhoid Fever (aka, Enteric Fever) is commonly caused by S. enterica serotype Typhi (S. Typhi).

The serotypes Paratyphi A, B and C cause a similar clinical picture but in general, are less severe. Treatment is as per S. Typhi.

There are also hundreds of other non-typhoidal Salmonella serotypes that commonly cause infective gastroenteritis (diarrhoea) and bacteraemia only develops in approximately 5% of cases.

Non-typhoidal Salmonellae have a broad range of animal hosts whereas S. Typhi and Paratyphi A and B are restricted to human hosts only.

S. Typhi is transmitted via faecal-oral route from those that are clinically unwell with the disease as well as asymptomatic carriers. Those organisms that survive exposure to stomach acid pass through to the small bowel where they adhere to Peyers patches in the distal ileum and then cross into the lymphatic system where they multiply. They enter the blood stream via the thoracic duct and are carried to the bone marrow, spleen, liver and gallbladder. Here the organisms are able replicate and re-enter the blood stream causing the onset of symptoms. A secondary invasion on the bowel occurs due to the infected bile excreted into the small intestine. An strong inflammatory response occurs at the Peyer’s patches which can lead to necrosis, ulceration and eventually perforation. To add insult, foci of inflammation called ‘typhoid nodules’ are scattered in various organs including the liver, spleen, marrow, lymph glands, myocardium, kidney, lung and brain which can cause not only local inflammation but also abscess formation. 

Chronic carriers may shed bacteria for decades and are responsible for most of the transmission of the bacteria in infected faeces.

Mary Mallon (23 September 1869 –11 November 1938) 

Mary was the first person in the United States to be identified as an asymptomatic carrier of typhoid and worked from 1900 to 1907 as a cook for affluent families. Outbreaks of typhoid occurred where she worked and she would often then move onto a different family.

In 1906 a family hired typhoid researcher George Soper, who believed Mallon might be the source of the outbreak, linking her to all the outbreaks but failed to convince her to provide urine and stool samples.

In 1907 she was finally arrested and quarantined for 3 years by which point she had large media attention and the nickname ‘Typhoid Mary’ was given.

On February 1910 Mallon agreed to change her occupation and was released. Unfortunately the provisions for a new career in a laundrette did not provide the same career satisfaction nor pay and she returned to cooking. She was arrested again and refused to have a cholecystectomy. Her second quarantine lasted from 1915 to 1938 when she died of stroke aged 68.

Brooks J. The sad and tragic life of Typhoid Mary. CMAJ. 1996 Mar 15; 154(6): 915–916. [PMC1487781]

Symptoms begin 7-14 days post ingestion.
The classic description of progressive Typhoid fever:

Week one: Stepwise rising fever. Common symptoms include; Headache, cough, abdominal pain, vomiting and malaise.
(Exam tip – any question involving a fever + cough + GI symptom the answer is Typhoid)

Week two: High grade fever (around 40 celsius with a relative bradycardia), obvious abdominal symptoms (can be diarrhoea or constipation), hepato-splemomegaly,  and Rose spots from day 7 (30% of patients).

Rose spots: Truncal salmon-coloured, blanching maculopapules usually 1-4 cm wide. Present in up to 30% of patients by the end of the first week.

Week three – complication week (10-15%): GI bleed, bowel perforation due to Peyer patch necrosis and pneumonia.

Fourth week: Advanced illness, ‘Typhoid state’ – apathy, confusion and psychosis. The typhoid facies. Neurological and intestinal complications may continue for months. 

Mortality rate in the post antibiotic area is approximately 1%. Pre-antibiotics, mortality rates were 15% or more. Classically the fever drops at the third week and the patient will begin to recover, the complications can be varied and death most commonly results from perforation, haemodynamic shock either from intestinal haemorrhage or toxaemia (occasionally from meningitis). 

Summary of the clinical picture:

• Average incubation is 14 days.
• The only consistent feature is fever. It’s gradual and increases day by day in the first week, often with an evening rise. A high sustained fever then continues for another week and falls by the 3rd or 4th week. 
• Patients with typhoid generally feel very unwell, generalised aches, anorexia, abdominal pain, headache, diarrhoea or constipation and a non-productive cough are common. 

If typhoid fever is suspected (e.g. fever plus travel to endemic area), 2-3 sets of blood cultures should be taken.

The number of bacteria in the blood is low (median 1 bacterium/ml) and various studies quote the sensitivity as low as 54%. A way of increasing this is to do large volume (30ml) blood culture 2-3x to increase the sensitivity to 80-90%.

A bone marrow biopsy can also be performed with sensitivities at 86% (10x higher bacterial load than blood) and can remain positive after antibiotics are started.

Stool and urine cultures can be tested but are limited in the acute setting, They are valued in the evaluation of chronic carriers. A positive test does not differentiate between an acutely ill patient and a chronic carrier with a separate illness.

Aspirates from rose spots, cerebrospinal fluid or pus from accesses may also yield positive cultures.  

The Widal test is a serological test used in developing countries to detect anti-S. Typhi antibodies (somatic O and Flagellar H). This test has limited clinical efficacy as it reflects not only current infection but also previous infection, it has a high rate of false positive and false negative results and can also be affected by the typhoid immunisation. In general its use should not be recommended.

Rapid test kits (from the Cochrane review): TUBEX showed an average sensitivity of 78% and specificity of 87%. Typhidot studies, grouped together to include Typhidot, Typhidot-M, and TyphiRapid-Tr02, showed an average sensitivity of 84% and specificity of 79%. Test-It Typhoid and prototypes (KIT) showed an average sensitivity of 69% and specificity of 90%.
Based on these results, in 1000 patients with fever where 30% (300 patients) have enteric fever, we would expect Typhidot tests, on average, to miss the diagnosis (give a false negative result) in 66 patients with enteric fever, TUBEX to miss 66, and Test-It Typhoid and prototypes (KIT) to miss 93. In the 700 people without enteric fever, the number of people incorrectly given a diagnosis of enteric fever (a false positive result) would be on average 161 with these Typhidot tests, 91 with TUBEX, and 70 with the Test-It Typhoid and prototypes (KIT).  The RDTs evaluated are not sufficiently accurate to replace blood culture as a diagnostic test for enteric fever.

These usually occur from the 3rd week onwards if the patient is not recovering. 

• Perforation – requires surgical excision and segmental resection plus brand spectrum antibiotics to cover GI organisms.
• Haemorrhage – from repeated small bleeds, often managed with transfusions.
• Haemolytic anaemia – especially in those with G6PD
• Lobar pneumonia
• Meningitis – maybe the only signs typhoid disease, particularly in the young.
• Renal disease – immune complex nephritis
• Typhoid abscess – can occur anywhere, a late complication.
• Skeletal – arthritis, osteomyelitis and polymyositis. 

One lecturer asked the question to his audience “Name a complication of typhoid”, a few scattered answers emerged, all were right but silence soon fell over the room, with a sigh the lecturer stated:

For the complications of Typhoid, think of an organ and add ‘itis’ and you won’t be wrong”

Typhoid fever can be treated with fluoroquinolones, third generation cephalosporins or azithromycin. There is increasing resistance to fluoroquinolones in S.E Asia so a third generation cephalosporin such as ceftriaxone 50-80 mg/kg/day is a reasonable first line antibiotic for most cases.

Severe cases require IV therapy for at least 10 days.  

Uncomplicated cases acquired from areas other than S.E Asia may be treated with ciprofloxacin 20 mg/kg/day. Azithromycin 20 mg/kg/day is a reasonable oral antibiotic choice for uncomplicated cases from most areas and although there are concerns to use it in paediatrics there have been no adverse outcomes reported for its limited use in this context. 

Patients with enteric fever who are still sick after 5-7 days of adequate fluroqinolone (ciprofloxacin, ofloxacin, levofloxacin and gatifloxacin) are likely to be resistant.

As there are increasing levels of multidrug resistant organisms it is important to direct antibiotic choice based on susceptibilities. In particular some of the older drugs that had resistance are now showing some sensitivity (Amoxicillin, co-trimoxazole and chloramphenicol).

What about steroids?
For the obtunded patient a small study in Indonesia with high dose dexamethasone showed some benefit. 3 mg/kg over 30 minutes followed by 1 mg/kg every 6 hours for 8 further doses. 

There are three vaccines available:

Ty21a – live oral attenuated strain:
Enteric coated capsule (5 years and older)
Liquid (2 years and older) – 3-4 doses over 5 days with a booster every 5 years.
33-67% vaccine efficacy (capsule) – 62% after 7 years
53-78% vaccine efficacy (liquid) – 78% after 5 years

Vi conjugate vaccine:, more effective than Vi vaccine (>90%). Conjugated to TT
Can be used in children from 6 months
Several manufactured in India
Vi-TT received WHO pre-qualification and SAGE recommendation

Purified Vi vaccine – polysaccharide antigen:
2 years or older
A single intramuscular injection. Repeat after 3 years
Vaccine efficacy 72% (Nepal); 64% (S.Africa) – 55% at 3 years; 69-71% (China)

Chronic carriers occur in 1-3% of those infected and are defined as faecal or urinary positive after 1yr since infection. The infection often smoulders on in the gallbladder but can also occur in the urinary tract with an association with Schistosoma mansion and haematobium causing relapsing non-typhoidal septicaemia. 

Treatment involves drug susceptibilities and requires a prolonged course of antibiotics e.g. ciprofloxacin 750 mg twice daily for 28 days. Alternative drug regimens often require 3 months of treatment. If the focus is in the gallbladder with cholelithiasis then a cholecystectomy is required to provide complete eradication. 

However, if the patient is conscientious and not a food handler, fastidious maintenance of  hygiene will prevent transmission and no further treatment is required.

He requires x2 negative stool cultures 48 hours apart before being allowed to handle food again.

Blood cultures subsequently isolated S. Typhi sensitive to ceftriaxone, azithromycin and amoxicillin and resistant to ciprofloxacin. He had an uneventful 5 day stay in hospital where he was treated with IV ceftriaxone before being discharged home on azithromycin.

Public health was notified and duly performed contact tracing. He was cleared to returned to work 2 weeks following discharge and promised to get his Typhoid fever vaccine in the future.