Towards a Strategic Plan for Research to Support the Global Program to EIiminate Lymphatic FiIariasis: Summary of Immediate Needs and Opportunities for Research on Lymphatic Filariasis. 2.2 Essential tools – Drugs and Clinical Drug Trials

A series of advances during the past decade transformed LF from a neglected disease of poor countries into a disease now recognized as potentially eradicable. Principal among the reasons for these advances were the identification of ivermectin and albendazole as new, effective anti-filarial agents and the discovery of new virtues for an old anti-filarial drug, DEC (i.e., its single-dose efficacy and macrofilaricidal action). These discoveries were essential for the subsequent creation of the Global Program to Eliminate LF,1 whose very basis is the large-scale use of DEC, ivermectin (Mectizan�; Merck and Co., Inc., Rahway, NJ) and albendazole. Indeed, in many endemic countries literally millions of tablets of these drugs are distributed over a few short days each year (often on a single day), making GPELF the largest chemotherapy program ever undertaken. Currently it is just these three drugs that are available for use in single-dose, annual MDA programs. Albendazole is co-administered with ivermectin in areas of Africa and Yemen where LF and onchocerciasis are co-endemic. For all other LF-endemic regions, albendazole is co-administered with DEC. At the recommended dose levels, none of the drugs is completely macrofilaricidal, although all appear to inflict some lasting damage to adult worms. Both DEC and ivermectin kill mf efficiently; albendazole, on the other hand, has no direct effect on mf, but rather appears to suppress embryogenesis in the adult female worm. An alternative treatment strategy involving the use of DEC as a fortificant in table/cooking salt for a period of 1−2 years is currently used in just one country, but was a mainstay of the earlier, successful LF elimination program in China

Eosinophils and the lung in tropical pulmonary eosinophilia

Tropical pulmonary eosinophilia (TPE) is commonly seen in areas endemic for filariasis. It must be remembered that the respiratory manifestations are part of a systemic disease characterised by marked increase in the blood eosinophil counts, malaise, fever and weight loss in addition to the respiratory symptoms. The clinical and laboratory features of the disorder have been extensively reviewed

Immunology of occupational lung diseases caused by dust: an overview

The lungs are exposed to numerous injurious substances.Such injury may be the result of immunological or non-immunological mechanisms. The lung clears itself of inhaled particles by means of ciliated cells lining the airways and the macrophages.The latter play an important role in the immune process as well.Inorganic particles are ingested by macrophages and if found inert are transported for eventual expulsion.Particles such as silica are poorly handled by macrophages, they not only damage the macrophages but also impair their function. Others, such as asbestos, may stimulate fibrosis. Endogenous factors such as the presence of auto-antibodies (rheumatoid factor or anti-nuclear factor) alter the response of the host to inhaled particles.The pathological changes caused by handling inorganic dusts include intestitial fibrosis, nodular fibrosis or macule formation leading to emphysema.Occupational asthma a occurs when individuals are exposed to dusts during the course of their work. The lung responds differently to organic dust. T cells and complement are important elements in handling organic dust.The role of inhaled steroids which have no significant systemic effects in the prevention of certain occupational asthmas is worth evaluating, apart from control measures which minimise the exposure

Skin changes in chronic lymphatic filariasis

Seventeen men and 31 women with unilateral lower limb lymphoedema attributed to chronic lymphatic filariasis were examined in the filarial out-patient clinic of the Government General Hospital, Madras, India. Skin changes such as skin fold thickening, hyperkeratosis, hypo-or hypertrichosis, pachydermia, pigmentary changes, chronic ulceration, epidermal and sub-epidermal nodules, and clinical intertrigo were observed and compared between the different lymphoedema grades. These lesions are not specific to chronic lymphatic filariasis, and have been described in other conditions displaying lymphostasis. They are thought to be favoured by secondary infections, which should be dealt with appropriately to prevent the progression of the disease and the onset of elephantiasi

Transcriptional Control of Impaired Th1 Responses in Patent Lymphatic Filariasis by T-Box Expressed in T Cells and Suppressor of Cytokine Signaling Genes

T-bet (T-box expressed in T cells) and GATA-3 are transcription factors that play a critical role in the development of Th1 and Th2 cells, as do genes of the SOCS (suppressor of cytokine signaling) family, albeit indirectly. Another transcription factor, Foxp3, is a master regulator of natural regulatory T cells (Tregs). To identify the role of these factors in impaired Th1 responses of patent filarial infection, analysis of cytokine, SOCS, and transcription factor mRNA expression was performed on purified T cells of filaria-infected individuals (n � 6) and uninfected controls (n � 6). As expected (and in contrast to cells of uninfected individuals), there was a significant depression of gamma interferon (IFN-�) and a concomitant increase in interleukin-4 (IL-4), IL-5, and IL-10 mRNA expression following stimulation with parasite antigen (BmA) but not with a polyclonal T-cell (anti-CD3) stimulus. T-bet (but not GATA-3) was expressed at significantly lower levels in cells of filaria-infected individuals in response to BmA compared with those from the uninfected group, accounting, at least partially, for the diminished IFN-� expression. Second, we found no significant differences in expression of Foxp3 between the two groups, although induction of Foxp3 expression correlated with induced expression levels of IL-10, implicating Tregs in the IL-10 expression seen. Finally, parasitespecific T-cell expression of SOCS-1, SOCS-5, and SOCS-7 was significantly diminished among infected patients; in contrast, expression of SOCS-3 increased. Our data therefore indicate that the impaired Th1 responses observed in patent lymphatic filariasis are associated with decreased expression of T-bet, SOCS-1, SOCS-5, and SOCS-7 and increased expression of SOCS-3 in T cells

Parasite specific energy in human filariasis; insights after analysis of parasite antigen-driven lymphokine production

The antigen-specific immune unresponsiveness seen in bancroftian filariasis was studied by examining lymphokine production in peripheral blood mononuclear cells (PBMC) or PBMC subpopulations from 10 patients with asymptomatic microfilaremia, 13 patients with elephantiasis and 6 normal North Americans. In each group of patients, the kinetics of the lymphokine response and the response to mitogens and nonparasite antigens did not differ significantly. In marked contrast, when antigeninduced lymphokine production was examined, most patients with microfilaremia were unable to produce either interleukin 2 (IL- 2) or y-interferon (i.e., were nonresponders), and the few who could (hyporesponders, generally with quite low microfilaremia levels) did so at levels significantly less than those of patients with elephantiasis, all of whom showed strong responses to parasite antigen. Removal of neither adherent cells or T8+ cells affected the parasite-specific anergy seen in those with microfilaremia, suggesting a state of T cell tolerance to the parasite in patients with this most common clinical manifestation of bancroftian filariasis

A Qualitative Study on the Feasibility and Benefits of Foot Hygiene Measures Practiced by Patients with Brugian Filariasis

Disability alleviation is an important component of Global Programme for Elimination of Lymphatic Filariasis'. In Brugia malayi infection the disability is largely due to acute attacks of adenolymphangitis (ADL), which frequently prevent patients from attending their normal activities, causing much suffering and economic loss. The foot care programme has been shown to reduce the frequency and severity of these episodes. In the present study we used semi-structured interviews to evaluate the impact of the foot care in 127 patients with brugian filariasis. They were previously trained in this procedure and were advised to practice it regularly, unsupervised. All except one could recollect the various components of foot hygiene and were practicing it regularly. They were aware of the factors causing ADL attacks and were able to avoid them. Majority (95.2%) expressed their happiness with the relief provided by foot care, which prevented or reduced the ADL episodes. The motivation was such that they transmitted this knowledge to others suffering in the community and even physically helped them to carry out foot care. This study fully endorses the advocacy of foot care programme as an easy to carry out, effective, sustainable and economically feasible ,procedure to prevent acute ADL attacks

Ivermectin in the treatment of Bancroftian filariasis infection in Orissa, India

Ivermectin treatment has evaluated for its efficacy and side reactions in sixty patients of Orissa with Bancroftian filarial infection and microfilaremia. Ivermectin was administered as a single oral dose at four dosage levels (20, 50. 100 and 200 μg/kg), and both microfilarial clearance and associated side reactions were monitored in a double blind fashion. Blood microfilariae were cleared in all patients at all dosages within 1 to 14 days. In most patients microfilariae reappeared by third month. The microfilaria appearance by third and sixth month averaged 12.2 to 44 percent of pretreatment values in the fourstudy groups. Side reactions were encountered in almost all patients, the commonest being fever. headache, weakness, myalgia and cough which occured most prominently 12 to 72 hours after treatment. Side reactions were more frequent and severe in patients with high microfilaria counts. Clinical reaction scores for each group were independent of the dose administered. The 200 μg dose group showed significantly more rapid microfilariae clearance and its delayed reappearance as compared with the other dosage groups and without inducing significantly greater clinical reaction scores

Urticaria - some observations

Urticaria has been known from antiquity. The disorder was known to the Arabs as essera and it has found a place in the writings of Cesius (circa 30 BC–45 AD). Although the condition was recognised as an entity, its cause was a mystery to the physicians of those times. It was initially thought to be a manifestation of idiosyncrasy and later believed to be a form of neuroses. However, now the pathophysiological basis of urticaria is well understood. The development of antihistamine group of drugs, paved the way for the management of urticaria

Estimation of ASO titer as an indicator of streptococcal infection precipitating acute adenolymphangitis in brugian lymphatic filariasis

Recurrent episodes of acute adenolymphangitis (ADL) are important clinical manifestations of lymphatic filariasis which contribute significantly to the progression of lymphedema. It is increasingly being recognized that secondary bacterial infections play an important role in the etiology of ADL. We examined the role of streptococcal infection as a precipitating factor of ADL in brugian filariasis, by determining the anti-streptolysin O (ASO) titers and by isolating the causative organism wherever possible. The study population consisted of 30 patients with filariasis related ADL (Group A), 30 patients with chronic filarial edema (Group B) and 60 age and sex matched healthy adults (Group C). ASO titer was estimated by the latex agglutination method at the time of entry into the study, at the 15th day and at 3,6 and 12 months. ASO titers were persistently elevated in 90% of patients in Group A and a portal of entry for bacterial infection was detected in all of these patients. In Group B only six patients had persistently elevated ASO titers. These patients had grade III lymphedema and three of them had monilial infections in the affected limb. In the control group none had persistently elevated ASO titers. The elevated ASO titers and the detection of a site of entry for bacteria in patients with ADL supports a streptococcal etiology for this condition