The Gastroenterologist rang the Microbiologist in a state of excitement, “we have a patient who we think has Whipple’s disease” he exclaimed. “How do we send samples?”
“Why do you think the patient has Whipple’s disease?” asked the grumpy Microbiologist (it had been a long day!).
Not put off by the Microbiologist's lack of enthusiasm the Gastroenterologist went on to explain about their patient with diarrhoea, weight loss, abdominal pain and no other diagnosis.
“Okay, okay, send samples to us in normal saline and send some to the Histopathologists as well” replied the Microbiologist...“but you do know how rare Whipple’s disease is, don’t you?”
“Why do you think the patient has Whipple’s disease?” asked the grumpy Microbiologist (it had been a long day!).
Not put off by the Microbiologist's lack of enthusiasm the Gastroenterologist went on to explain about their patient with diarrhoea, weight loss, abdominal pain and no other diagnosis.
“Okay, okay, send samples to us in normal saline and send some to the Histopathologists as well” replied the Microbiologist...“but you do know how rare Whipple’s disease is, don’t you?”
Whipple’s disease was first described by George H. Whipple back in 1907 and although he suspected there might be an infectious cause it wasn’t until 1960 when bacteria were first identified (using an electron microscope) as the cause of the disease. But it was a long wait, until the 1990s, before science actually identified the bacterium responsible (Tropheryma whipplei) using 16sRNA PCR as the bacterium could not be cultured. Finally in 2000 a stable method of culture was established and further work could be done to learn more about it.
Tropheryma whipplei is rod shaped and has a membrane outside of a cell wall similar to Gram-negative bacteria; it is in the family of Actinobacteria. The bacterium is very slow growing taking 18 days to double in number (E. coli numbers double in 20-30 minutes!). It is still not certain but the most likely place for this replication to take place in humans is within macrophages in the gut wall as well as possibly in peripheral blood.
Curiously T. whipplei appears to be able to rearrange its genetics, easily allowing it to get around immune responses and survive against selective pressures in the environment… clever little bug! …I am getting to the foam frenzy, honest!
Where does T. whipplei live?
T. whipplei is thought to be an environmental organism and if you look it is frequently found in sewage. It is thought that faecally contaminated soil is the main source of exposure for humans either directly or through contaminated food. Humans are the only known host of T. whipplei. Patients with Whipple’s Disease shed the bacterium in stool and saliva so human-to-human transmission is very likely to occur. Up to 10% of healthy people have detectable bacteria in their stool, so not everyone exposed gets infection, most just become colonised.
So if T. whipplei is so common why is Whipple’s Disease so rare?
Despite T. whipplei being found readily in the environment the prevalence of Whipple’s disease is about 1 in 1 million! This is because exposure to the bacterium only leads to infection if you are genetically predisposed to infection, and this genetic predisposition is actually the bit that is very rare. Immunosuppression with steroids and other immune-modulating drugs can also increase the risk of infection although it is not yet fully known why or by how much.
How does Whipple’s disease present?
There are a number of different presentations of Whipple’s disease:
Classical Whipple’s disease predominantly affects the gastrointestinal tract with diarrhoea, weight loss and abdominal pain. Malabsorption leading to hypoproteinaemia, ascites and peripheral oedema are common. Low grade fevers, joint pains, anaemia and intra-abdominal lymphadenopathy can also occur.
Extraintestinal Whipple’s disease can occur in the central nervous system, joints and heart either in combination or separately. There are a whole host of CNS symptoms that can occur but the most specific are supranuclear ophthalmoplegia (inability to consciously move the eyes) and facial myorhythmias (uncontrolled contractions of the facial muscles). The main type of joint involvement is inflammation of the small joints of the hands and feet. Cardiac involvement is usually in the form of destruction of the mitral or aortic valve leading to heart failure.
How is Whipple’s disease diagnosed?
The most important part of diagnosing this very rare condition is to consider it in the first place (maybe the grumpy Microbiologist should have given the Gastroenterologist some brownie points for thinking about it!). Because the clinical features can mimic all sorts of other diagnoses Whipple’s disease is often not thought about. In fact the average time from developing symptoms to diagnosis can vary from 12 months for diarrhoea to over 6 years for joint pains!
The most useful samples for diagnosing Whipple’s disease are multiple duodenal biopsies taken at endoscopy. Samples should be sent to microbiology in normal saline and to histopathology in 10% formal saline. DO NOT send microbiology samples in 10% formal saline as the formaldehyde interferes with the diagnostic test!
Diagnosis of Whipple’s disease is based on a 2 stage testing regimen, although if clinically suspected both stages can be performed at the same time.
The first line test is usually histological examination for typical foamy macrophages in the lamina propria of the duodenum (yes, really, this is the only mention of foamy frenzy…sorry to disappoint… but at least you started reading the blog!). If this is positive then confirmation with second line tests of either T. whipplei specific immunohistochemistry by histopathology using particular antibodies or by microbiology using T. whipplei PCR is required. If the second line test is negative then the alternative second line test should be tried and a “best 2 out of 3” result accepted! PCR and histology can also be performed on sterile tissue or fluids from extraintestinal sites.
Can Whipple’s disease be treated?
Antibiotic treatment of Whipple’s disease is very effective with symptoms resolving within days to weeks. Treatment is based around an initial 2 week IV induction phase of therapy followed by 12 months oral treatment.
Tropheryma whipplei is rod shaped and has a membrane outside of a cell wall similar to Gram-negative bacteria; it is in the family of Actinobacteria. The bacterium is very slow growing taking 18 days to double in number (E. coli numbers double in 20-30 minutes!). It is still not certain but the most likely place for this replication to take place in humans is within macrophages in the gut wall as well as possibly in peripheral blood.
Curiously T. whipplei appears to be able to rearrange its genetics, easily allowing it to get around immune responses and survive against selective pressures in the environment… clever little bug! …I am getting to the foam frenzy, honest!
Where does T. whipplei live?
T. whipplei is thought to be an environmental organism and if you look it is frequently found in sewage. It is thought that faecally contaminated soil is the main source of exposure for humans either directly or through contaminated food. Humans are the only known host of T. whipplei. Patients with Whipple’s Disease shed the bacterium in stool and saliva so human-to-human transmission is very likely to occur. Up to 10% of healthy people have detectable bacteria in their stool, so not everyone exposed gets infection, most just become colonised.
So if T. whipplei is so common why is Whipple’s Disease so rare?
Despite T. whipplei being found readily in the environment the prevalence of Whipple’s disease is about 1 in 1 million! This is because exposure to the bacterium only leads to infection if you are genetically predisposed to infection, and this genetic predisposition is actually the bit that is very rare. Immunosuppression with steroids and other immune-modulating drugs can also increase the risk of infection although it is not yet fully known why or by how much.
How does Whipple’s disease present?
There are a number of different presentations of Whipple’s disease:
- Classical
- Extraintestinal
- Acute gastroenteritis
- Acute pneumonia
Classical Whipple’s disease predominantly affects the gastrointestinal tract with diarrhoea, weight loss and abdominal pain. Malabsorption leading to hypoproteinaemia, ascites and peripheral oedema are common. Low grade fevers, joint pains, anaemia and intra-abdominal lymphadenopathy can also occur.
Extraintestinal Whipple’s disease can occur in the central nervous system, joints and heart either in combination or separately. There are a whole host of CNS symptoms that can occur but the most specific are supranuclear ophthalmoplegia (inability to consciously move the eyes) and facial myorhythmias (uncontrolled contractions of the facial muscles). The main type of joint involvement is inflammation of the small joints of the hands and feet. Cardiac involvement is usually in the form of destruction of the mitral or aortic valve leading to heart failure.
How is Whipple’s disease diagnosed?
The most important part of diagnosing this very rare condition is to consider it in the first place (maybe the grumpy Microbiologist should have given the Gastroenterologist some brownie points for thinking about it!). Because the clinical features can mimic all sorts of other diagnoses Whipple’s disease is often not thought about. In fact the average time from developing symptoms to diagnosis can vary from 12 months for diarrhoea to over 6 years for joint pains!
The most useful samples for diagnosing Whipple’s disease are multiple duodenal biopsies taken at endoscopy. Samples should be sent to microbiology in normal saline and to histopathology in 10% formal saline. DO NOT send microbiology samples in 10% formal saline as the formaldehyde interferes with the diagnostic test!
Diagnosis of Whipple’s disease is based on a 2 stage testing regimen, although if clinically suspected both stages can be performed at the same time.
The first line test is usually histological examination for typical foamy macrophages in the lamina propria of the duodenum (yes, really, this is the only mention of foamy frenzy…sorry to disappoint… but at least you started reading the blog!). If this is positive then confirmation with second line tests of either T. whipplei specific immunohistochemistry by histopathology using particular antibodies or by microbiology using T. whipplei PCR is required. If the second line test is negative then the alternative second line test should be tried and a “best 2 out of 3” result accepted! PCR and histology can also be performed on sterile tissue or fluids from extraintestinal sites.
Can Whipple’s disease be treated?
Antibiotic treatment of Whipple’s disease is very effective with symptoms resolving within days to weeks. Treatment is based around an initial 2 week IV induction phase of therapy followed by 12 months oral treatment.
Initial therapy |
Antibiotic |
1st Line |
IV Ceftriaxone 2g OD |
2nd line (if 1st line contraindicated) |
IV Meropenem 1g TDS |
Long-term therapy |
Antibiotic |
1st Line |
PO Co-trimoxazole 960mg BD |
2nd line (if 1st line contraindicated) |
PO Doxycycline 200mg OD PLUS PO Hydroxychloroquine 600mg OD |
The main side-effect of the treatment of Whipple’s disease is the Jarisch-Herxheimer reaction (high fever and anaphylaxis like reaction) within 24 hours of starting treatment due to the rapid lysis of bacteria and subsequent immune response. If the patient was immunosuppressed prior to developing Whipple’s disease then an immune reconstitution inflammatory syndrome (IRIS) can occur within 3 weeks following an initial period of improvement due to the patient’s immune system recovering and suddenly kicking into overdrive and making the patient unwell.
Untreated Whipple’s disease is fatal but treatment is very effective. Relapse after treatment is rare, occurring in only 1-2% of patients, but can happen up to 30 years after stopping treatment so patients should be followed up regularly with repeat duodenal biopsies at 6 months, 12 months and then at longer intervals.
Our patient underwent a duodenal biopsy and the histology and PCR were both negative. A diagnosis of Whipple’s disease was excluded but the Gastroenterologists where not too put out, they were pleased as punch that they thought of the diagnosis in the first place! Whipple’s disease is very rare after all…!
PS only one of the editorial team has ever been to a foam party… and it wasn’t the Microbiologist!
Untreated Whipple’s disease is fatal but treatment is very effective. Relapse after treatment is rare, occurring in only 1-2% of patients, but can happen up to 30 years after stopping treatment so patients should be followed up regularly with repeat duodenal biopsies at 6 months, 12 months and then at longer intervals.
Our patient underwent a duodenal biopsy and the histology and PCR were both negative. A diagnosis of Whipple’s disease was excluded but the Gastroenterologists where not too put out, they were pleased as punch that they thought of the diagnosis in the first place! Whipple’s disease is very rare after all…!
PS only one of the editorial team has ever been to a foam party… and it wasn’t the Microbiologist!
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