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Zinc against diarrhoea and tropical diseases

May 24, 2015 - 07:41 -- Pierre Lutgen

DIARRHOEA

On October 23 , 2014 WHO issued a recommandation (www.who.int/elena/titles/zinc_diarrhoea) stating that mothers, other caregivers and health workers should provide children with 20 mg per day of zinc supplementation for 10-14 days (10 mg per day for infants under the age of six months).

Finally !

In May 2004 a UNICEF document (P Froes,MD, UNICEF/TACRO) had already summarized several studies and concluded that zinc-supplemented children had 24% lower probability of continuing diarrhoea and 42% lower rate of treatment failure or death. Supplementary zinc benefits children with diarrhoea because it is a vital micronutrient for essential immune functions and intestinal transport of water and electrolytes. Zinc supplementation is even more more efficient if accompanied by oral hydratation solutions (ORS) containing salts and glucose. The efficacy of zinc against enteric bacterial pathogens causing diarrhoea. In vitro it inhibits their growth at 0.1 microgr/liter (U Faiz et al., J Ayub Med Coll 2011, 23-2, 18-21).

Some people (Policy Paper E2Pi August 2014) wonder why international health institutions (Global Fund, World Bank, UNITAID, RBM, Bill&Melinda Gates) scaled up artemisinin-combination-therapy but ignored zinc/oral rehydratation therapy although diarrhea causes more child deaths each year than malaria. The WHO Child Health Epidemiology Group gave for 2004 and the total number for under-5 mortalities : malaria 888 300, diarrhea 2 162 000 deaths.

A recent survey on the external funding of international health agencies (CC Unger et al., Arch Dis Child 2014 99-3, 273-8) estimated that between 2007 and 2011, HIV/AIDS received US$ 6500 million, malaria 1300 million and zinc treatment 15 million. We quote a paper from India „The curious case of zinc for diarrhea: unavailable, unprescribed and unused. » B Gitanjali et al., J Pharmacol and Pharmacotherap, 2011, 2-4, 225-229). Diarrhea kills nearly 650 children below the age of 5 years per day in India. Only a minuscule 1% are prescribed zinc during an episode of diarrrhoea because it is hardly available. The authors relate this to the fact that the pharmaceutical industry has no interest to promote this treatment. The average price per treatment is $US 0.15.

Zinc deficiency is associated with an increased risk of gastrointestinal infections, adverse effects on the structure and function of the gastrointestinal tract, and impaired immune function.. Zinc inhibits gastric acid secretion and increases the gastric pH. (P Kirchhoff et al., Amer J Gastroenterol, 2011, 106. 62-70). This was observed not only in vitro but also in 12 healthy volunteers. The effect of zinc chloride is apparent within seconds after drug intake and continues for about 3 hours.

ZINC AND THE IMMUNE SYSTEM

Zinc has a pivotal role in the entire immune system fostering resistance to infections by virus, fungi and bacteria. Zinc functions as an antioxidant. It protects cells of damaging effects of oxygen radicals generated during immune activation. But the human body has no zinc storage system, hence, a daily nutritional zinc uptake is necessary. The immune system is strongly impaired by zinc deficiency, predominantly the cell-mediated response by T-lymphocytes. This leads to a reduced CD4 cell count and T-cell numbers, a decreased ratio of type 1 to type 2 T-helper cells with lower production of T-helper type 1 cytokines like interferon-gamma, and compromised T-cell mediated immune defense. Accordingly, disturbed zinc homeostasis increases the risk for infections, and zinc supplementation restores normal immune function. Furthermore, several disorders, like mycobacterial infections, asthma, diabetes, and rheumatoid arthritis are accompanied by decreased zinc levels and in some cases disease progression can be affected by zinc supplementation (A Hönscheid et al., Endocr Metab Immune Drug Targets, 2009, 9-2, 132-44). Th1 activation stimulates macrophages, which have a pivotal role in phagocytosis of aggressors. A high CD4+/CD8+ ratio is indicative of improved immune activity. Zinc stimulates the immune system and increases CD4 (E Mocchegiani et al., J of Nutrition, 2000, 1424-1430

This might be one of the reasons why human milk is rich in zinc. UNICEF estimates that a formula-fed child living in unhygienic conditions is between 6 and 25 times more likely to die of diarrhea and four times more likely to die of pneumonia than a breastfed child (Wikipedia, 2007).The zinc content of milk varies with species, lower in cow milk, and stage of lactation, much higher in colostrum. This is probably contributing to the immunity of newborns against malaria.

Zinc supplementation improves the cellular immune status, raises CD4 and the CD4/CD8 ratio as it was found in a ramdomly set trial with 76 children in an Indian slum . This might explain the impact on diarrheal morbidity (Sazawal et al., Indian Peediatr, 11997, 34, 589-97). Zinc gluconate lowers the aspartate AST and alanine aminotransferase ALT values (K Laoprasopwattana et al., PLOS, 2013.7-6, e2287)

Plants from the Artemisia family increase the CD4 count as several of our partners have demonstrated (Constant Tchandema, Patrick Ogwang, Felicitas Roelofsen, unpublished data). Aqueous extracts from leaves or seeds of Artemisia annua increase the secretion of IFN-gamma, more than pure artemisinin (M Islamuddin et al., PLOS Neglected Tropical Diseases, 2015). IFN-gamma is an important activator of macrophages. There may be several reasons for this immunostimulatory effect.

Artemisia plants are very rich in zinc, more than most vegetables, and are sometimes considered as hyperaccumulators. This could explain the prophylactic effect which has been noticed for regular consumption of infusions of these plants. ARTAVOL a prophylactic drug against malaria in Uganda is composed of three plants rich in zinc: artemisia, avocado and lemongrass.

Another hypothesis is that polysaccharides present in medicinal plants and particularly in several Artemisia species, up to 2% on dry weight, might play a role. They release IFN-gamma and increase its bioactivity. Several authors have noticed a striking enhancement of IFN-gamma production. (JJ Shan et al., Yao Xue Xue Bao, 2002, 37, 497-500).(Im Sun-A et al., J of Immunology, 2007, 178, 95.29). Polysaccharides from ginseng also modulate IFN-gamma (W Zhang et al., Planta Med 2007, 73-1). They increase the ratio of CD4 to CD8 (Y Qiu et al., Poultry Science, 2007, 86, 2530-35). In a recent paper Artemisia annua polysaccharides were used as an adjuvant in hepatitis C vaccination. They can widely regulate the humoral and cellular immunity. They promote IFN-gamma secretion probably by inducing Th1-type cellular immune response (Bao LD, et al., Genet Mol Res. 2015 May 11;4957-65).

HELMINTHS

The immunity against nematodes is expressed at the intestinal level in a complex series of responses that impair worm fecondity and initiate worm expulsion. At the parenteral level it may reduce the number of larvae that successfully migrate to and encyst in skeletal muscles.

Zinc supplementation reduces the intensity of Schistosoma mansoni reinfections. This finding probably reflects a biological effect of zinc that could be of public health importance in settings with higher transmission (H Friis et al., Eur J Clin Nutrit, 1997, 51, 33-37). In a trial mice were maintained on zinc deficient diets for eight weeks post schistosomiasis infection. Zinc-deficient mice experienced stunted growth, reduced weight gain and higher granula formation. The low level of zinc in the diet also affected the humoral immune response of the host to schistosome egg antigens. ( O Nawar et al., Am J Trop Med Hyg. 1992 Sep;47(3):383-9 )

In rats zinc deficieny was shown to impair the expulsion of Trichinella spiralis (PK Fenwick et al., Am J Clin Nutr 1990, 52, 166-72). Compared to the control rats, concentration of Cu, Zn, Co and Mn were significantly lower in the liver of rats infected with Fasciola hepatica

LEISHMANIASIS

The Universidad de Antioquia in Colombia has obtained first positive in vivo results (submitted to Biomedcentral for publication, May 2015) against leishmaniasis with capsules containing Artemisia annua powder. The plant is rich in zinc and this might stimulate the macrophages which leishmaniasis is able to desactivate by pushing the Th2 immunity pathway. Zinc is known for ist wound healing properties (AB Landsown et al., Wound Repair Regen. 2007 Jan-Feb;15(1):2-16).

In Brazil (J van Weyenbergh et al, BMC Infectuous Diseases, 2004, 4-50) a significant decrease in plasma Zn was observed for leishmania patients. The authors confirmed that Zn acts as a monocyte/macrophage activator, and the decrease in Zn in many patients might be responsible for the inability of the patients to clear the parasite. But they observed in parallel that in some patients plasma Cu increased to levels which have been shown to be toxic in vitro. At these concentrations in vivo IFN-gamma production is decreased, implying that increases in Cu levels might augment susceptibility to infection with intracellular pathogens.

In India it was also observed that serum zinc levels were significantly lower in leishmania patients (J Mishra et al., Indian J Med Res 2010, 131, 793-798). It appears that leishmaniasis has found a way to mislead the immune system. Only macrophages are really capable to destroy the invading parasites. But these send a signal called LACK to the T CD4 lymphocytes, interrupting the activation of macrophages (E Mougneau et al., Science, 1995, 268, 563-566). For this same reason, leishmania parasites are able to evade the host immune system in low zinc conditions where the phagocytic macrophage count is low.

LEPROSY, TUBERCULOSIS, BURULI ULCER

In Mycobacterium diseases similar decreases in plama Zn and increases in plasma Cu were observed (George J1,Int J Lepr Other Mycobact Dis. 1991 Mar; 59:20-4). A significant reduction in serum zinc levels was noticed in all types of leprosy. Conversely, the copper levels were significantly increased. After oral zinc therapy, the serum zinc levels were significantly increased in the patients. In contrast, the copper levels were not decreased, indicating that oral zinc therapy can restore normal zinc levels in leprosy patients but is unable to reduce the increased copper levels.

The Institut Pasteur has shown that the immune cells are capable of mobilizing reserves of heavy metals, especially zinc, to poison microbes. In macrophages that have ingested M. tuberculosis or E. coli, the researchers observed a rapid and persistent accumulation of zinc. Zinc, although toxic when ingested in too high quantities, is therefore beneficial for the immune system, particularly because it is used by macrophages to poison microbes.

Oral zinc was tried in 15 cases of multibacillary leprosy (NK Mathur et al., Int J Lepr Other Mycobact Dis. 1984 Sep;52(3):331-8) as an immunostimulant in addition to conventional antileprosy drugs. Results were compared with those in ten similar cases treated with dapsone alone. Cases treated with zinc showed faster clinical improvement. Upgrading occurred in 6 out of 15 patients taking zinc, but in only 1 out of 10 patients in the control group.

For pulmonary tuberculosis a study from Mexico (RX Armijos et al., Salud PublicaMex 2010 May, 52) showed that earlier elimination of bacilli from sputum was associated with improved zinc status and TH1 immune response. The therapeutic effect of vitamin A was less evident. If confirmed in clinical trials, this adjuntive therapy could be used to shorten the amount of time that TB patients are contagious,

The effectiveness and success of antituberculosis therapy is mainly measured by its ability to identify the organism in the sputum. Another research team (Ciftci TU et al., Biol Trace Elem Res. 2003 Oct;95(1):65-71) found that during treatment there was a significant increase in the levels of Zn and a decrease in the Cu/Zn ratio. Serum Zn levels and the Cu/Zn ratio could be used as a valuable laboratory tool for the clinicians to assess response to therapy or effectiveness of the ongoing antituberculosis therapy.

The effect of zinc on Buruli ulcer (Mycobacterium ulcerans) has barely been studied. As zinc is known for therapeutical properties in many skin diseases, this would deserve further research. Zn can be a useful topical or oral treatment in common warts (KE Sharpie et al., Saudi Medical Journal, 2007, 28, 1418-21). Our partners in Kenya have seen similar effects for juice expressed from Artemisia annua leaves. Oral more than topical use of zinc oxide cures Acne vulgaris. Topical treatment with green tea lotions apears to be very efficient (M Gupta et al. Dermatology Research and Practice, 2014, ID709152).

MALARIA

Infections such as malaria may be more sensitive to zinc deficiencies because the killing by macrophages is inhibited.

Malaria is associated with a rapid decline in CD4 cell count (J Mermin et al., JAIDS, 2006, 41, 129-130). CD4+ T cells that produce interferon γ and interleukin 2, but not interleukin 4, can reduce parasites in vivo (Chakrit Hirunpetcharat et al.,Proc Natl Acad Sci U S A. 1998 Feb 17; 95(4): 1715–1720). Zinc deficiency exarcerbates experimental malaria infection in mice (AH Shankar et al., FASEB J, 1995, 9 A4269). Plasma zinc concentrations are depressed during the acute phase response in children, as was observed on a cohort of 689 children from Ghana, Tanzania, Zambia (C Duggan et al, J Nutr 2005, 135, 802-7). The authors relate this hypozincemia to release of Il-8 in the acute phase. The University of Louvain has shown that the Artemisia annua from Luxembourg poor in artemisinin causes the strongest IL-8 inhibition when compared to teas from other origins (PM de Magalhaes et al., Food Chemistry 2012, 134, 864-871).

The supplementation of zinc on morbidity due to Plasmodium falciparum was studied in Papua New Guinea. It resulted in a reduction up to 69% of P falciparum health-center based episodes (AH Shankar et al., Am J Trop Med Hyg2000, 62-6, 663-669). . Zinc supplementation and prophylaxy seems to work better against Plasmodium vivax than P falciparum (SA Richard et al., Am J Trop Med, 206, 75, 126-132). Treatment with zinc-desferrioxamine lowers parasitemia and parasite growth (M Chevion et al., Antimicrob Agents and Chemotherap, 1995, 39, 1902-5). The particularity of the parasite Plasmodium is that not only Zn but also Cu deprivation (H Asaki et al., BMC Microbiology, 2014, 14 :167) hampers its thriving. Artemisia plants as was said previously are accumulators of heavy metals and are generally 10 times richer in Zn than in Cu.

CONCLUSION

The results of zinc supplementation as recommended and documented by many papers are beneficial in several diseases. Unfortunately zinc products are barely available in rural communities. But plants from the Artemisia family are hyperacccumulators and can provide this supplement of zinc and other essential metals like selenium, copper.

The objective should be : have Artemisia plants growing in every garden in tropical countries.