What's New in Control, Management, and Elimination of Tropical Diseases?
By Jay S. Keystone, MD, MSc
On december 6-7, 1997, the american committee on Clinical Tropical Medicine and Travelers' Health of the American Society of Tropical Medicine and Hygiene sponsored a two-day update on tropical medicine. The course, organized by Ann Moore, Phyllis Kozarsky, and Susan Stokes, consisted of 14 speakers on subjects ranging from the global problem of emerging infectious diseases to a symposium on vaccines for tropical diseases. The following review will cover the highlights of this meeting.
Infectious Diseases: A Threat at the Turn of the Century
David Heymann, MD, Director, Division of Emerging and Other Communicable Diseases, Surveillance and Control, World Health Organization, outlined the factors responsible for emerging and re-emerging infectious diseases: 1) the weakness of the public health infrastructure for infection control (e.g., mosquito control in Latin America and Asia with re-emergence of dengue); 2) population increases and rapid urbanization (resulting in a breakdown of sanitation and water systems in coastal cities in Latin America, Asia, and Africa promoting the transmission of cholera and shigellosis); 3) man-made or natural effects on the environment ranging from global warming and consequent extension of vector-borne diseases to ecological changes due to deforestation that increase contact between man and animals (Ebola virus epidemic in Zaire, Lyme borreliosis in Europe and North America, and Hantavirus pulmonary syndrome in North America); and 4) changes in human behavior (the emergence and amplification of HIV world-wide linked directly to unsafe sexual practices.)
The emergence and re-emergence of infectious diseases are amplified by two major factors: the continuing and increasing evolution of antimicrobial resistance and dramatic increases in international travel. In 1988, a clone of multi-resistant Streptococcus pneumoniae first isolated in Spain was later identified in Iceland. Forced migration has led to widespread epidemics of cholera in Africa and Kala Azar in South Sudan. In 1994, in a refugee population of between 500,000 and 800,000 in Rwanda, an estimated 60,000 developed cholera in the first month after the influx, and an estimated 33,000 died.
Dr. Heymann pointed out that eradication and elimination cannot substitute for good public health: rebuilding of the weakened public health infrastructure and strengthening of water and sanitary systems; minimizing the effect of natural and man-made changes of the environment; effectively communicating information about prevention of infectious diseases; and appropriately using antibiotics.
Treatment of Leishmaniasis
Barbara Herwaldt, MD, a leishmaniac from the CDC, provided a comprehensive update of the therapy of leishmaniasis, both cutaneous and visceral. Because of the complexity of leishmaniasis treatment literature, she emphasized the need to be cautious in interpreting what one reads and in generalizing results to other settings, syndromes, and species than those that were studied. For the treatment of visceral leishmaniasis, sodium stibogluconate (Sb) is the first-line treatment, as is amphotericin B or, preferably, lipid-associated amphotericin. The second-line therapy for visceral leishmaniasis is Pentamidine, Sb plus Aminosidine, or Sb plus interferon-gamma. For old world cutaneous leishmaniasis, the first-line drug is Sb and the second-line, paromomycin/MBCL, intralesional Sb, or perhaps another local treatment such as heat or cryotherapy. For new world cutaneous leishmaniasis, Sb is the primary treatment or, if the infection is L. panamensis, a short course of pentamidine (3 mg/kg every other day for 4 doses). The second-line therapy for L. panamensis or L. mexicana is ketoconazole. Intraconazole was not shown to be effective for L. braziliensis and offered little advantage for L. mexicana. Allopurinol has not lived up to expectations. CDC provides clinical consultation and assistance in diagnosis (770-488-7760).
Combined Use of Ivermectin and Albendazole
David Addiss, MD, from the CDC indicated that in lymphatic filariasis control, ivermectin alone will not produce sustained suppression of W. bancrofti microfilaremia as suggested in early clinical trials. The addition of a single dose of albendazole (400-600 mg) to ivermectin (400 mcg/kg) led to a microfilarial reduction of more than 99% one year after treatment in Sri Lanka and 99% in Haiti four months after treatment, compared with 76% for the group that received only ivermectin. The combination of albendazole and ivermectin also looks promising for enhanced efficacy against T. trichiura leading to increased nutritional benefit in children with this infection.
Practical Perspectives on Protozoan Parasites
Jay Keystone, MD, MSc, from the University of Toronto, reviewed recent advances in amebiasis, giardiasis, cyclosporiasis, and blastocystosis. He reminded participants that 90% of microscopically diagnosed E. histolytica are a morphologically identical nonpathogen now identified as E. dispar. These parasites can be differentiated by stool antigen and DNA detection. Amebic serology is the most readily available test to distinguish the two parasites in that 100% of asymptomatic E. histolytica carriers will be seropositive compared with 25% of those carrying E. dispar. Larger epidemiological studies are needed to confirm this finding. A review of ancient and recent literature suggested that a single dose of metronidazole (2.5 g) is sufficient to treat amebic liver abscess, and the same dose given once daily for three days cures 90-95% of those with amebic colitis. Five days of standard dose metronidazole (750 mg tid) has been shown to cure 100% of those with amebic liver abscess and 93% of those with amebic colitis.
For giardiasis, single-dose metronidazole (2 g in adults) administered once daily for three days provides the same cure rate and side effects as a standard five-day course of treatment. This single-dose regimen is ideal for children, who tolerate metronidazole poorly; those under 25 kg require 35 mg/kg (in a single dose daily for 3 days), and those between 25 and 40 kg require 50 mg/kg/d. Alternative therapies for giardiasis include tinidazole, furazolidone, albendazole, and possibly praziquantel. A one-week course of albendazole, 400 mg/d, appears to have a 96-100% cure rate for giardiasis.
A review of two recent epidemics of cyclosporiasis indicates that it's a berry-imported cause of "traveler's diarrhea," with an incubation period that can be as short as two days and a clinical picture of relapsing, cyclical diarrhea. In AIDS patients, infection is considerably prolonged, with increased diarrhea and possible involvement of the biliary tract. Diagnosis by fluorescent microscopy of blue auto-fluorescing organisms or safranin stain appear to be more effective than the modified acid-fast technique, which stains the organisms variably. A one-week course of cotrimoxazole has been shown to be very effective, but trimethoprim alone has failed.
In a review of Blastocystis hominis, the speaker noted that it is a ubiquitous, highly prevalent enteric protozoan likely transmitted through the fecal/oral route. The majority of infections appear to be asymptomatic. Work in animal models and recent genetic studies suggest that there is a potential for this organism to be pathogenic. However, the definitive study to determine pathogenicity in humans, a randomized, double-blind, placebo-controlled treatment trial, has not been done because treatment is uniformly unsatisfactory. Current therapies, iodoquinol, metronidazole, paromomycin, cotrimoxazole, and furazolidone are no more than 50% effective when used individually.
Recent Advances in Lymphatic Filariasis
Gerusa Dreyer, MD, from Recife, Brazil, reviewed the pathogenesis of lymphatic filariasis and showed that the original hypothesis, lymphatic blockage with dilatation and fluid extravasation into tissues, no longer holds in view of recent ultrasonography and pathologic studies. Using ultrasonography of the scrotum, she has shown that there is no obstruction of lymphatic vessels but, rather, reversible dilatation of lymphatic channels. Also, lymphangectasia does not always correlate with location of worms. Dr. Dreyer hypothesized that cytokines or some other substance may be responsible for lymphatic dilatation and leakage.
In the diagnosis of W. bancrofti infection, recent studies have shown that detection of circulating filarial antigen appears to be more sensitive in identifying actively infected individuals. Also, antigen detection tests are more convenient because the concentration of filarial antigen in peripheral blood does not exhibit significant periodical variation. Thus, collection of blood at night is not required. These features make antigen detection assays particularly attractive for rapid epidemiological assessment and for exploring clinical features of the disease. A recent study in Brazil showed that an ELISA test was 97.9% sensitive in those with detectable microfilaremia and 66.7% positive in those who had no microfilaremia but evidence of adult worm infection. The specificity appears to be 98.4%.
Treatment studies of bancroftian filariasis have been revolutionized by ultrasonographic examination of male scrota. Drug efficacy can now be determined directly by assessing viability of adult worms. These studies have shown that a single dose of diethylcarbamazine, (6 mg/kg) will be effective in 50% of infections. Above 6 mg/kg, there was no significant increase in worm death. Thus, a significant proportion of adult bancroftian filaria worms are not susceptible to DEC. There is some suggestion that repeated single doses of DEC at six- to 12-month intervals may increase the drug's efficacy. Finally, Dr. Dreyer's groundbreaking studies have shown that 97% of those with acute episodes of adenolymphangitis are due to bacterial infections in patients with long-standing lymphadema. Prophylactic antibiotics, rigorous foot care (especially with control of T. pedis) exercise, and leg elevation have been shown to reduce dramatically lower limb elephantiasis due to Bancroftian filariasis.
Viral Hemorrhagic Fevers
R. Swanepoel, MD, from the Special Pathogens Unit, National Institute for Virology, South Africa, reviewed the current approach to viral hemorrhagic fevers. He pointed out that the vast majority of suspected cases of VHF turn out to be severe cases of more common infections such as bacterial septicemia, leptospirosis, severe measles, and other rickettsial infections. The importance of obtaining an accurate clinical history cannot be over-emphasized; the exact dates and details of events constituting potential exposure to infection should be noted and also the exact timing of onset of illness. He pointed out that those with viral hemorrhagic fevers often travel in rural areas and are exposed to livestock, rodents, ticks, and mosquitoes. Suspicion is heightened when there is a definite history of tick or insect bites or contact with blood and other tissues of animals. Frequently, VHF infections are encountered in predictable circumstances (i.e., when there is a massive outbreak in an area or when a healthcare or laboratory worker has had a needlestick during the management of an infected individual).
Clinical presentation of viral hemorrhagic fevers is relatively non-specific. Individuals often present with sudden onset of illness marked by severe headache, high fever, myalgia, arthralgia, conjunctivitis, abdominal pain, and maculopapular or petechial rash on the trunk. Ecchymoses or purpuric rash and other signs of bleeding do not usually occur until the second week of illness. The incubation periods usually fall in the range of 5-14 days but can be as short as 1-3 days (Congo Crimean Hemorrhagic Fever) or three weeks (Lassa and hantavirus infections). Diagnosis of VHF is usually made by viral antigen detection or PCR. Antibodies are usually not positive for at least one week. Some viruses are susceptible to ribavirin (Lassa fever, Congo Crimean Hemorrhagic Fever, and Argentinian Hemorrhagic Fever). Medical staff at all levels must be familiar with basic barrier-nursing techniques, so that preliminary isolation of suspected VHF patients can be instituted pending the outcome of laboratory investigations.
Current Issues in the Diagnosis, Management, and Control of American Trypanosomiasis (Chagas Disease)
Lou Kirchhoff, MD, Professor of Medicine at the University of Iowa, reviewed the growing problem of American trypanosomiasis, especially as it is seen in immunosuppressed persons. Dr. Kirchhoff reminded us that acute Chagas disease is usually a mild febrile illness with a case fatality ratio of less than 5%, but chronic Chagas cardiomyopathy occurs in approximately 10-30% after years or even decades of infection. Immunosuppression of persons who chronically harbor T. cruzi can lead to a recrudescence of infection, frequently with an intensity that is typical of severe acute Chagas disease in persons who are not immunocompromised. Severe multifocal or diffuse meningoencephalitis, cutaneous lesions, myocarditis, and fulminant disease are seen in immunocompromised patients. Although ELISA, IFA, and complement fixation tests are highly sensitive for Chagas disease, they are not very specific; therefore, a confirmatory test such as a radioimmune assay or precipitan test is necessary. PCR appears to be very sensitive but is not readily available. Xenodiagnosis and hemoculture have a sensitivity of 50% and 50-90%, respectively. When the diagnosis is suspected in HIV-positive patients, blood, CSF, tissue, and effusions should be examined for trypanosomes.
Current therapy for T. cruzi is unsatisfactory, and treatment is recommended only for patients with acute or early indeterminant phase infections. Consideration should be given for treating those with latent infections of less than 10 years duration. Benznidazole is the drug of choice. Fluconazole, itraconazole, and allopurinol are not useful.
Finally, Dr. Kirchoff reviewed the problem of transfusion-related Chagas disease as noted in blood bank studies in the United States. Various studies have shown a prevalence of Chagas antibodies from a high of one in 560 Hispanic surname donors in southern and western United States to one in 8806 among 300,000 blood donors in Miami and Los Angeles. It has been recommended that blood banks add a questionnaire to screen out those who may have been exposed to Chagas disease. However, recent studies have shown that Chagas-infected donors do not always understand the questionnaire or may be untruthful in their responses.
Symposium on Vaccines for Tropical Diseases
Duane Gubler, MD, from the Division of Vector-borne Infectious Diseases, CDC, indicated that considerable progress has been made in recent years in developing a vaccine for dengue. Effective vaccination to prevent DHF will require a tetravalent, live attenuated vaccine. Promising candidate attenuated vaccine viruses have been developed and have been evaluated in phase 1 and 2 trials in Thailand. A commercial formulation is currently undergoing repeat phase 1 and 2 trials. Progress has also been made on developing second generation, recombinant dengue vaccines by using cDNA infectious clone technology. Despite these studies, it is unlikely that an effective, safe, and economical dengue vaccine will be available in the near future. Therefore, other approaches to disease prevention, particularly personal protection measures against insect bites during early morning and late afternoon in urban centers, is of primary importance.
Stephen Hoffman, MD, from the Walter Reed Army Institute of Medical Research, Bethesda, MD, reviewed current approaches to the development of a malaria vaccine. He indicated that an ideal malaria vaccine will induce immune responses against each stage of the plasmodium species life cycle and that different arms of the immune system are required to attack the parasite at the different stages. Therefore, a multi-stage vaccine must be a multi-immune response vaccine. In addition, given the unique antigenicities of the different stages of the life cycle, the vaccine must be multi-valent. The current three approaches to vaccine development include vaccines targeted against selected antigens of asexual stages of the parasite, and transmission blocking vaccines targeted against gametocytes, gametes, or later stages in mosquitoes. To date, only a single vaccine, SPf66 aimed at the erythrocytic phase of the disease has been reported in multiple clinical trials. Vaccine efficacy has ranged from as low as -9% in Thailand to a high of 55% against P. falciparum in Venezuela. Vaccine efficacy was 8% and 31% in Gambian infants and children in Southern Tanzania, respectively.
Studies in the early 1970s showed that humans could be protected against malaria through exposure to large numbers of irradiated sporozoites. Recently, a recombinant fusion of the circumsporozoite protein with hepatitis B surface antigen in adjuvant was tested in human volunteers. In this preliminary study, six out of seven subjects who received the vaccine in combination with immune stimulants were protected against experimental challenge with P. falciparum sporozoites.
Dr. Hoffman went on to indicate that the new technology of DNA vaccination appears to offer the best prospect for development of a multivalent vaccine that effectively activates both humoral and cell mediated arms of the immune system. The demonstration that "DNA plasmids can induce antigen encoded specific immune responses following intramuscular or intradermal injection or following administration of DNA on gold particles" has led to considerable enthusiasm about this approach. The simplicity of the DNA approach implies that it is possible to combine many DNA sequences, each encoding different antigens, (multivalent) from one or more stages of the life cycle (multi-stage) and then broaden the immune response (multi-immune response). There are, however, potential safety concerns related to the use of DNA as an immunogen, particularly the potential for random integration of the injected DNA into the host chromosome, resulting in the activation of oncogenes or the inactivation of tumor suppressor genes. Other concerns include the possible adverse consequences associated with the long-term persistence of a foreign antigen, and the induction of tolerance, autoimmunity, or hyperimmunity. These safety issues will need to be addressed and resolved before the technology of DNA vaccination is widely accepted for human use.