Tropical Sprue

OVERVIEW: What every practitioner needs to know

Symptoms associated with tropical sprue include chronic diarrhea and symptoms of malabsorption; including steatorrhea, cramps, bloating, and ultimately, weight loss. Because tropical sprue may be accompanied by anemia, symptoms can also include pallor, fatigue, and weakness. Many times, these symptoms result in the occurrence of anorexia. The definition of tropical sprue requires the presence of a chronic diarrheal illness, residence in or prolonged travel to an endemic area, and malabsorption of two or more nutrients.

Physical signs associated with tropical sprue may include a distended abdomen and hyperactive bowel sounds. Pallor due to anemia may be present; in longstanding disease, signs related to malabsorption of nutrients may be present and include glossitis, stomatitis, and dermatitis. In extremely prolonged disease, peripheral neuropathy may also occur. Fever is rare in tropical sprue.

How did the patient develop tropical sprue? What was the primary source from which the infection spread?

Tropical sprue, as named, occurs only in individuals who have had prolonged exposure in the tropics; while it is more common individuals who live in the areas of risk, it has occurred in travelers who have spent more than 1 month in a tropical area.

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Tropical sprue is most common in Asia and the Caribbean. Areas of specific risk within Asia include the Indian subcontinent, from Nepal to South India. In this area, outbreaks have been linked to particular extended families or to sequential families living in a specific house within a village. Tropical sprue has also been common in Myanmar and the Philippines, where outbreaks in US military personnel and their families have occurred. In the Caribbean, the populations of Puerto Rico, Haiti, and the Dominican Republic appear to be at high risk. Although one of the original descriptions of tropical sprue in the Caribbean was in Barbados, it is no longer seen there. The disease is rarely diagnosed in Central America or Mexico. The diagnosis of tropical sprue is being made less frequently at present; this is thought to be related to improvements in access to clean water and better hygiene, as well as access to antibiotics and medical care. While tropical sprue is rare in Africa, it has been reported in Tanzania, South Africa, and in expatriates in Nigeria. A sprue-like illness has also been reported in Turkey. There also appears to be a seasonality to the diagnosis of tropical sprue. In a 4-year outbreak that was seen in US military personnel in the Philippines, the diagnosis was made more frequently from March to July than in other months of the year. There also appears to be a seasonality to the presentation and diagnosis of tropical sprue in Puerto Rico.

Which individuals are at greater risk of developing disease tropical sprue?

Individuals who reside in or are immigrants from areas of endemic tropical sprue are at greatest risk of developing disease; immigrants may develop tropical sprue some time after leaving an area of risk. Expatriates who have lived in an endemic area for longer than 6 months are at highest risk for tropical sprue although disease has occurred in travelers who have been in an area of risk for as little as 2 to 4 weeks. Tropical sprue has occurred in US military personnel in the Philippines and Vietnam and in Peace Corp volunteers. Individuals who have intestinal immune deficiencies, such as deficiency of secretory immunoglobulin A, may also be at increased risk. This suggests other causes than an infectious etiology, but limits the possibility that generalized malnutrition predisposes individuals to acquire tropical sprue. There does not appear to be a genetic predisposition to tropical sprue, another factor which distinguishes it from gluten-sensitive enteropathy (celiac sprue).

Beware: there are other diseases that can mimic tropical sprue:

Gluten-sensitive enteropathy (also known as celiac sprue)

Infections with Giardia lamblia, Strongyloides stercoralis, Isospora belli, Cryptosporidium parvum, and Cyclospora cayetanensis.

Human immunodeficiency virus (HIV) infection (untreated)

Intestinal lymphoma

Small bowel overgrowth

Intestinal dysmotility syndromes or blind loop syndrome

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Peripheral white blood cell count with differential; anemia is the most common laboratory finding in tropical sprue, anemia is usually megaloblastic as folate and vitamin B₁₂ malabsorption occur early, if disease is advanced, iron malabsorption may also occur and anemia may become normocytic. If vitamin B₁₂ malabsorption is severe, pancytopenia may occur

Folate deficiency is required to make the diagnosis

Vitamin B₁₂ deficiency

Serum albumin may be low

Calcium levels may be low

Vitamin D may be low

D-xylose testing may be abnormal

No evidence of parasitic infection in stool (no Giardia, Cyclospora, Strongyloides, Cryptosporidium, or Isospora)

Stool fat may be positive (72 hour collection >7g/day)

Antibodies to endomysium, transglutaminase, and/or gliadin are negative

HIV serology should be confirmed as negative

The use of breath hydrogen testing for documentation of small bowel overgrowth remains controversial, and if positive is suggestive but not diagnostic of tropical sprue

Results that confirm the diagnosis

An upper endoscopy should be performed in cases of suspected tropical sprue; however, even positive findings may be suggestive but are not diagnostic of tropical sprue. In an individual with flattened duodenal folds on upper endoscopy, small intestinal biopsy may also show shortened, blunted villi and elongated crypts with inflammatory cells in the lamina propria. If upper endoscopy is performed, aspirates of duodenal fluid should be examined for parasites.

Response to treatment of tropical sprue with folgate and tetracycline is required to confirm the diagnosis of tropical sprue. Treatment with folate alone improves the symptoms of tropical sprue, but the diarrhea continues.

What imaging studies will be helpful in making or excluding the diagnosis of tropical sprue?

An upper GI series with small bowel follow through can suggest the diagnosis of tropical sprue if it shows flattened mucosal folds, luminal dilation, or flocculation of the barium meal. As with endoscopy, the upper GI series is suggestive but is not diagnostic and is not absolutely required.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Infectious disease and GI consults may be useful in making the diagnosis of tropical sprue.

If you decide the patient has tropical sprue, what therapies should you initiate immediately?

The presentation of tropical sprue is a chronic one, so there is rarely an emergent need to initiate antibiotic therapy. However as there is no one diagnostic laboratory test or procedure, empirical therapy is indicated in a patient with symptoms, signs, and laboratory abnormalities consistent with tropical sprue and no other obvious pathogenic process. The definition of tropical sprue includes prolonged diarrhea, appropriate epidemiology, and the malabsorption of two or more nutrients, with folate and vitamin B₁₂ being the most common nutrients malabsorbed. In this setting a trial of tetracycline 250mg orally four times daily and folic acid 5mg/day can be considered. If response to this regimen is positive, therapy should be continued for 1 month in travelers and for 3 to 6 months (or longer) for residents of endemic areas, as relapses are known to occur. A positive response to this treatment regimen is considered to confirm the diagnosis of tropical sprue.

There are anecdotal reports of the use of rifaximin to treat tropical enteropathy, which is slightly different than tropical sprue, but there are no head to head trials of rifaximin vs tetracycline to suggest that there is any benefit to using rifaximin rather than the less expensive tetracycline.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

2. Other key therapeutic modalities

If there is significant vitamin B₁₂ deficiency present in the patient with tropical sprue, the use of vitamin B₁₂ injections may be needed

What complications could arise as a consequence of tropical sprue?

What should you tell the family about the patient's prognosis?

The major concern with treatment of tropical sprue in individuals who continue to live in endemic regions is the possibility of relapse. This potential is why the recommended duration of therapy for individuals living in endemic areas is prolonged.

The complications of tropical sprue are those related to the malabsorption that is part of the syndrome. Weight gain may occur slowly as intestinal function recovers. The anemia usually responds to the repletion of folate and vitamin B₁₂ although severe vitamin B₁₂ deficiency may require intramuscular repletion. Neuropathy may not remit even after repletion of folate and vitamin B₁₂ but is unlikely to progress.

What-if scenarios:

If there is no response to treatment with folate and tetracycline, the diagnosis of tropical sprue becomes very unlikely and other causes of persistent diarrhea and malabsorption must be revisited.

How do you contract tropical sprue and how frequent is this disease?

Tropical sprue is becoming less common than previously, even in endemic areas, but it still occurs in endemic areas. India still reports a signficant number of cases of tropical sprue and anecdotal evidence in Puerto Rico suggests the disease is still endemic there, as well. Residence in an area of risk with exposure to contaminated water and environment places an individual at risk for developing tropical sprue.

The onset of tropical sprue is often not subtle; an individual may report that one day they developed a diarrheal illness that went on to become persistent. The symptoms of malabsorption develop more slowly after this initial insult. While the epidemiology of tropical sprue suggests it is the region of residence or travel that is most important in the development of disease, there does appear to be a seasonality, at least in the Philippines and in Puerto Rico. In the Philippines, more cases appear to present in the spring, between March and July, although this seasonality is not understood.

While there are reports of houses in villages in South India in which serial dwellers all developed tropical sprue, the overall pathogenesis of the illness is not well understood, there is also no clear understanding of how the infections presumed to be responsible for the syndrome are transmitted. It is not known if there is transmission by contact with certain environmental factors, but only that poor hygiene and living in a contaminated environment appear to place an individual at risk.

What pathogens are responsible for this disease?

Most patients with tropical sprue appear to have Gram-negative bacteria such as Klebsiella, Enterobacter, or Escherichia. coli present in their small bowel; no particular toxin, adhesin, or other virulence factor has been identified with the pathogenesis of tropical sprue. As the response to treatment with the antibiotic tetracycline is diagnostic of the syndrome, there is a strong suggestion that there is a link between the presence of these bacteria in the small bowel and the pathogenesis of disease. It may be that studies with newer technology, such as advanced generation sequencing, may provide insight in this regard, as this technique can identify nonculturable organisms.

What is the pathogenesis of tropical sprue?

There is ample evidence to suggest that tropical sprue is caused by an enteric infection; the onset of the illness if often acute and begins with an acute diarrheal illness. There are endemic and epidemic regions of risk for tropical sprue; this might also suggest regional variations in some specific micronutrient that puts an individual at risk. Multiple studies of patients with tropical sprue have demonstrated small bowel overgrowth with Gram-negative organisms, which are not classically present in the small bowel. After the initial small bowel injury/enteric infection and the occurrence of small bowel overgrowth, malabsorption of specific micronutrients, particularly folate and vitamin B₁₂ occurs. Megaloblastic changes begin to occur in the small bowel, resulting in less efficient absorption of water, electrolytes, and carbohydrates. This is followed by more extensive malabsorption, and the result is the clinical presentation of tropical sprue.

What other clinical manifestations may help me to diagnose and manage tropical sprue?

The physical examination in tropical sprue is quite nonspecific; there is rarely fever and the patient is rarely so dehydrated as to cause abnormalities in pulse rate or blood pressure although orthostasis may occur in some cases. Conjunctival pallor may reflect anemia. The only other finding may be the presence of a distended although nontender abdomen with hyperactive bowel sounds. Specific findings associated with specific deficiencies of micronutrients may be present.

How can tropical sprue be prevented?

There is no vaccine for tropical sprue and no evidence exists to suggest that prophylactic antibiotics would be of value. Routine advice for travelers to observe good food and water hygiene should suffice.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Ramakrishna, BS, Venkataraman, S, Mukhopadhya, A. “Tropical malabsorption”. Postgrad Med J. vol. 82. 2006. pp. 779-87. (A current review of the differential diagnosis of tropical malabsorption and a context for tropical sprue within that framework. Written by investigators at an institution that has a long history of excellent work on the epidemiology and pathogenesis of tropical sprue in one of the highest risk regions.)

Ramakrishna, BS, Mathan, VI. “Water and electrolyte absorption by the colon in tropical sprue”. Gut. vol. 10. 1982. pp. 843-6. (Studies on the pathophysiology of tropical sprue, investigating the impact of small bowel disease on colonic function in tropical sprue.)

Banwell, JG, Gorbach, SL. “Tropical sprue”. Gut. vol. 10. 1969. pp. 328-33. (A review of the pathogenesis of tropical sprue written at the time of intense investigation in the etiology of the disease.)

Ghoshal, UC, Ghoshal, U, Ayyagari, A. “Tropical sprue is associated with contamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time”. J Gastroenterol Hepatol. vol. 18. 2003. pp. 540-7. (Studies on the pathophysiology of tropical sprue in patients with clinical diagnosis of tropical sprue, with comparisons to patients with irritable bowel syndrome demonstrating more bacterial contamination in the sprue patients, as well as more a longer orocecal transit time in this population which correlated with fecal fat. The abnormalities in the sprue patients normalized after treatment.)

Thakur, B, Mishra, P, Desai, N, Thakur, S, Alexander, J, Sawant, P. “Profile of chronic small bowel diarrhea in adults in Western India: a hospital based study”. Trop Gastroenterol. vol. 27. 2006. pp. 84-6. (Tropical sprue was the third most commons cause of chronic diarrhea in this recent study after intestinal tuberculosis and celiac disease.)

Kilpstein, FA, Falaiye, JM. “Tropical sprue in expatriates from the tropics living in the continental United States”. Medicine (Baltimore). 1969. pp. 476-91. (The clinical, laboratory and therapeutic response of 40 individuals diagnosed in the United States with tropical sprue. Controls included 50 asymptomatic expatriates from the West Indies.)

Klipstein, FA. “Absorption of physiologic doses of folic acid in subject with tropical sprue responsive to tetracycline therapy”. Blood. vol. 34. 1969. pp. 191-203. (Studies to define the appropriate dosage of folate for treatment of tropical sprue.)

Mathan, VI, Ignatius, M, Baker, SJ. “A household epidemic of tropical sprue”. Gut. vol. 5. 1966. pp. 490-6. (Epidemiology of epidemic tropical sprue in South India.)

DRG CODES and expected length of stay

Tropical sprue DRG 579.1; tropical sprue would only rarely require hospital admission if, for example, anemia was so severe as to cause cognitive symptoms.

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