TESTING FOR TYPHOID
On January 1, 2015 we began testing for typhoid fever in Mexico. This marks a step forward in the care we provide for our patients in the towns we serve there. There is a long story behind this, going back to the beginning of Mision de Candelilla in the 1980’s, but first a little about typhoid. This illness is classified as an indolent fever, along with several other bacterial infections that can take a slow course, persisting for months to years if untreated. Other indolent fevers include brucellosis and infections with proteus bacteria.
Typhoid results from infection with Salmonella typhi, a waterborne bacteria that only affects humans. This illness has long been eradicated from the US. A few cases of typhoid fever still seen here each year, all contracted by travellers to Asia or to Latin America, the remaining areas on the globe where typhoid remains endemic.
Typhoid starts after drinking contaminated water or eating food washed in contaminated water. After ingestion, the bacteria penetrate the intestinal lining, from there making their way through the body’s lymphatic system to the bone marrow, liver and spleen. It is in these organs that they set up the focus of infection. The symptoms are rather nonspecific, mainly fatigue and aching, but an infected person may feel intensely ill. Typhoid has a characteristic rash, but it may occur in only as few as ten per cent of the cases. There is usually fever in the initial stage of the infection, but little after that. It is said to feel like a low-grade case of influenza that goes on and on and on. The nonspecific nature of the illness can make it hard to even think of typhoid in evaluating a patient, even where it remains common.
The acute phase of typhoid may last as long as a month, and from there it goes on to become a chronic infection, mainly symptomatic with headache, joint pains, and fatigue. There is a carrier state as well, with little in the way of chronic symptoms but persistent shedding of the bacteria from the liver through bile. Sometimes the carriers are completely free of symptoms. The asymptomatic carrier state was originally identified in the case of Mary Mallon, a domestic cook in New York over a century ago. As she moved from house to house to cook for wealthy families in New York City and on Long Island, almost every family member developed typhoid. This was before the antibiotic era, so no treatment was available. She was restricted to life-long quarantine, but often escaped and spread typhoid again. She became known as Typhoid Mary.
A few cases were still occurring in Houston in my medical student days in the 1960’s. At that time we used a medical term FUO, which stood for “fever of unknown origin.” This was defined as a febrile illness lasting longer than one month, with no source detected for the fever after repeated medical evaluations over that period of time. In that day, FUO was an appropriate reason for admission to the hospital “for tests.” Diagnostic testing has evolved dramatically in the subsequent years, and I haven’t heard the term FUO in a long time. At any rate, I recall hospital admissions when I was a medical student for FUO, and we routinely tested such patients for typhoid.
The test for typhoid at that was called “febrile agglutinins.” In fact, this was a test for all the indolent fevers and it was designed to detect antibodies against the three bacteria. This test was the best we had in that time, but it was known from the beginning to be inaccurate. It was overly sensitive, often giving a positive test when in fact there were no antibodies against any of the three bacteria, and it was also known to miss a significant number of cases of indolent fevers. Evaluating febrile agglutinin results to make treatment decisions was complicated and uncertain. A positive test might signify persistently elevated antibodies from past exposure or illness that had long since resolved, or even a recent exposure without infection. The same result could also represent a current infection requiring treatment. Due to the inaccuracies of the febrile agglutinin test, doctors in the US abandoned it long ago, instead utilizing cultures for the bacteria, and more recently, tests to detect DNA fragments that are specific to typhoid. As a result, I haven’t heard of febrile agglutinins being used in the US for over thirty years. But the situation is different in Mexico.
There patients maintain their own medical records, including blood test reports and actual copies of X-Rays and scans (although they don’t maintain the doctors’ notes from their evaluations). As a result, since the early days of Mision de Candelilla, I have seen febrile agglutinin results brought by patients who had been tested by doctors in Musquiz. These patients would tell me of their fatigue and aching joints and they would show me the results of the febrile agglutinins. Over the years I have seen a number of reports positive for typhoid in patients from that area, occasionally a positive for proteus, but never a positive for brucella. When I have seen the positive reports for typhoid, I have puzzled over the cases, asking a lot of questions about other symptoms that might point to a different diagnosis. I have asked about their treatment, and I learned many couldn’t afford the prescribed antibiotics and came to us hoping we could give them the course of treatment. Some took a short course of antibiotics, maybe not being able to afford the whole prescription. I still encounter this test among our patients in Mexico to the present day, and am just as challenged now as I was then to provide appropriate care.
Knowing the limitations of febrile agglutinins, I have at times over the years looked for ways we might get more accurate evaluations on these people. One of the problems of simply treating for typhoid without knowing the correct diagnosis with any certainty is that the full course of treatment for typhoid is six weeks of two antibiotics. This is a therapy that can cause problems, including various antibiotic toxicities, an especially dangerous event for patients who must wait months between our visits. When I saw a patient who had symptoms suggestive of typhoid, I would be faced with starting the antibiotics with no diagnostic testing available to us. If the patient brought the results of his febrile agglutinin testing, I would puzzle over the vagaries of that outmoded test. I didn’t like it either way.
At various times over the years I searched for bedside tests for typhoid, something that would allow us to test for this disease on our trips where no sophisticated laboratory facilities exist. This would allow us to be more certain about the cases of suspected typhoid we saw, but nothing was ever available. We looked into drawing blood from the patients in Mexico for testing in the US, but this didn’t work out. Not only would it be difficult or impossible to communicate the test results to the patients in a timely manner, we also learned it would take a permit to bring biological specimens across the border, and we were advised this permit is difficult to get, likely only possible for medical research facilities.
About a year ago Thad Miller, a Mision de Candelilla board member and a tuberculosis researcher at the University of North Texas Health Science Center in Ft. Worth, heard of a bedside test for typhoid. In his work he has regular contact with the Centers for Disease Control in Atlanta, Georgia, and through his contacts there he learned a South African company had developed a rapid test for typhoid. Although we were unable to follow-up on that lead, my interest was piqued, once again.
Then in the summer of 2014 I saw a report of a rapid test for typhoid, something that came in the hundreds of medical news e-mails I receive. With a little research, I was able to contact the company in Sweden that makes the test, called TUBEX TF, with “TF” standing for typhoid fever. I learned that though the test is not licensed in the US or in Mexico, it can be bought for research purposes. I discussed this with Thad, and we quickly formulated a medical research study with our patients in Mexico, testing them with TUBEX TF if they seemed to have typhoid on the basis of their symptoms, and also performing the TUBEX TF test when we had patients bring us their febrile agglutinin test results, for comparison. We could test anyone who had a history of treatment for typhoid, and we could test some people at random who did not appear to have typhoid and had no history of the disease to see if we got positive results among people with no symptoms of or history of having typhoid. The main point was, since we would be doing this for research purposes, we would not use the tests for making the decision whether to treat the patients. At this time, we would be evaluating the test for its usefulness.
The tests came from Sweden in time for our Dec. 30, ’14 to Jan. 3, ’15 mission trip. Thad and I established a simple protocol to inquire at registration if any of our patients had a history of treatment for indolent fever (in Mexico, often simply referred to as fievre, meaning “fever, sometimes as fievre de Malta, and occasionally by the correct name fievre tiphoidea). We would ask such patients for permission to draw blood for the TUBEX TF testing, and we would also draw blood from the next patient with no history of indolent fever as a presumed true negative comparison sample. We were especially interested in testing any of the patients who brought us febrile agglutinin testing results so we could compare those results directly with the TUBEX TF testing. As we began to draw blood from the patients in Las Norias, I wondered if we might eventually identify a Tifoidea Maria in the area, maybe someone unknowingly spreading the disease across the desert of northern Mexico the same way the original Typhoid Mary did in New York.
We went to three towns on this trip, but only one clinic yielded patients meeting our testing criteria. This was Las Norias, where four of twenty-four patients seen reported past indolent fever treatment, and we drew a blood sample for each of these, as well as from four “true negative” patients. One typhoid patient had been treated twenty years ago, two about ten years earlier, and another we had treated about one year ago when he brought us his febrile agglutinin results. I saw him then and recorded his test results in our medical record. He told me he had never gotten over his symptoms of fatigue and aching joints, then he had worsened recently and had been tested in Musquiz again a month prior to our trip. He did not have his test results this time, but he reported the febrile agglutinin test had shown fievre tiphoidea. I decided to treat him again, this time with different antibiotics, with the presumptive diagnosis of chronic typhoid with a prior treatment failure.
TUBEX TF is a serum test, and it can be run soon after the blood has been drawn if the tube is spun in a centrifuge to separate the red cells from the serum. Blood left to stand a few hours in the collection tubes will separate as well, so serum can be easily obtained for testing later, even without a centrifuge. Since we would not be using the tests for our treatment decisions, I decided not to add a centrifuge to all the things we take on our trips already, but to just let the samples separate and do them all at the same time after clinic.
When I finally sat down to run the tests, I found the serum from a control patient was not usable because the red blood cells were broken up at the time of drawing the sample, and the serum was blood-stained (the test relies on detecting certain colors, and the redness of the serum for that patient’s test obscured the result). Of the others, all seven of our tests were negative for typhoid, including the man who got a six week course of antibiotics from us.
The decision to run the tests later led to an unexpected problem: despite our careful explanations prior to drawing blood, our patients all asked for the test results prior to leaving the clinic. We didn’t seem to be able to communicate to them the concept we were doing the testing to evaluate the test itself, that it wouldn’t make any difference in treatment if we had the results for them. They still wanted to know, and I disappointed them in this. Next time I’ll need to tell them something different, maybe that the results won’t be available until much later, or maybe we could tell them we’ll give them the results the next time we are there in Mexico. Or, maybe I might tell them the results would be available if they come by early the next morning before we leave their town to go to the next clinic.
It’s much too early to know how our study will go, but it appears possible, judging from the negative results we got on our seven patients, that we may not actually have typhoid in the towns we serve, and Tifoidea Maria may not exist. We may have been making inappropriate treatment decisions on the basis of false positive febrile agglutinin tests or on our clinical impressions of these patients. If this were true, the health risks these patients face does not come from typhoid, but rather from the unnecessary course of antibiotics indicated by a flawed and obsolete laboratory test that has given us the idea typhoid is endemic to this area.
We have seventy-two TUBEX TF tests, and if we use perhaps eight or ten per trip we’ll about use them up in the six medical trips we’ll do this year. As we gain more experience with the tests, the trends should become clearer. Thad and I plan to write a medical journal article about our study. It should be publishable, whatever the results. The company in Sweden that makes TUBEX TF is also interested in the results of this study, because they need clinical experience in order to proceed with marketing their product. We will see where it takes us. For now it is enough to know that this project has potential to yield real improvements to health and healthcare among the people we serve in Mexico.