Malaria in the malnourished
malaria in the malnourished Michael Golden 11.02.99
no title Kevin Marsh 12.02.99
Malaria and Malnutrition Tony Nelson 13.02.99
no title Kevin Marsh 17.02.99
Nutrition and Malaria - Synergism and Antagonism Nevin Scrimshaw 17.02.99


Date: Thu, 11 Feb 1999 11:35:08 +0000

From: Michael Golden <m.goldenatabdn.ac.uk>

Subject: Ngonut: malaria in the malnourished.

 

I think we should re-open the issue of malaria treatment where there are no diagnostic facilities at all and in the malnourished (see: Iron, folic acid and malaria, 1998).

I recently heard that severely malnourished children were at much higher risk from malaria than non-malnourished children - and there was little evidence that there was any "protective" effect. That without a "complete cure" of malaria (even though the parasitaemia drops to very low levels) that there is no recovery in haemoglobin levels, there is then a rebound in parasitaemia and that the haemoglobin then incrementally falls to very low levels. And that there is rapidly spreading resistance to Fansidar.

As with most infections in the severely malnourished there is hardly any relationship between parasitaemia and clinical signs.

The advice we had some time ago (from Kevin Marsh, Wellcome Trust Unit in Kilifi, Kenya) was that we should routinely use Fansidar for the severely malnourished in therapeutic feeding centres - where it is unusual to have a microscope, stain, slides etc, the patients are desperately vulnerable, there is a high prevalence of malaria when this has been surveyed and it is a relatively small proportion of the population. I would like to know what the present advice would be for this particular patient group.

On a wider issue, is there any policy on the distribution and use of impregnated bed-net/curtains in refugee/displaced person situations.

Prof. Michael H.N.Golden


From: "Kevin Marsh" <kmarshatafricaonline.co.ke>

Date: Fri, 12 Feb 1999 09:34:20 -0000

 

Mike raises the question of malaria treatment in malnourished kids. Our own experience is that malnutrition certainly does not protect against severe malaria-and in fact is a risk factor for it. This is not necessarily incompatible with some of the famous/nototious studies in the literature-it is possible that one could reach a state of extreme starvation where even the parasite can't happily thrive--but certainly in the kinds of severely malnourished children we see , malaria is at least as common and as severe as in any one else and probably more so.

Mike asked me a couple of years ago about treatment in the context of camps in areas where we knew chloroquine resistance was likely to be well advanced--usually on the basis of data from surveys in the same general area-such data rarely, if ever, being available in the actual population being treated. I felt that if there was significant malaria transmission going on then fansidar would be the treatment of choice-given that this is the direction that many central and east african countries are moving in for first line treatment. The ideal is obviously to have a diagnosis but this is not always possible and in the absence the choice is to do nothing, treat febrile cases or treat everyone. The first is not acceptable. the second would be standard practice for children with a fever anywhere where malaria is a problem. The third may be justified if a significant proportion of the children are parasitised ( again the problem of what would be a significant proportion?) because of the risk of continuing fall in haemoglobin levels with persisting parasitaemia.

Things change quickly-fansidar resistance is now developing rapidly in many areas of southern and eastern africa--this is potentially a disaster as there is very little affordable down the line. ( this is no surprise-everyone knew it would happen-the argument for switching to fansidar was that the increase in mortality due to chloroquine failure was so bad that one may as well have the benefit of five years or so of an effective treatment drug before returning back to the same position).

So what do you do in camps where there is malaria transmission?

I think the first thing is to establish what is the drug sensitivity position in the area--increasingly national control programmes are in a better position to give guidance and there is a lot of local variation so one can no longer give a blanket prescription.

The second thing is that there is an even greater need to try to establish some diagnostic facility--not necessarily for every case, but at least to establish the scale of the problem. The new diagnostic dip sticks such as parasight F are very good and in practice probably have comparable sensitivity and specificity to microscopy. They are relatively expensive but this has to be set against the problems of increasing resistance and the much greater expense of the next line of antimalarials.

Third, there is a strong move by many of us at the moment to push the idea of combination therapy for malaria ( same argument as for TB and HIV) Trials are being rushed through of fansidar plus artesunate ( even where there is resistance the theory suggests that the combination will be very effective)-- this is not far enough down the line to recommend it now--but the studies are being fast tracked all over africa and i guess there will be data within the year. in the meantime many feel it makes sense to use fansidar in combination with standard full dose chloroquine --there are two seperate argument here (1) the anti inflammatory effect of CQ makes you feel better quicker and (2) The rapid biomass reduction, which occurs even with the majority of CQ resistant parasites, reduces the chance of fansidar resistant parasites hanging on in there. the first bit is backed by data, the second not yet - but its a good bet and we do use this as standard treatment in Kilifi.

It is worth mentioning that in many areas where there is major CQ resistance sensitivity to amodiaquine remains surprisingly good--and some argue that this could have been an alternative to fansidar. i would not use it for any sort of mass administration given its history of toxicity when used as prophylaxis--but as treatment it is a good drug, though i can't comment on any partcular risks in malnourished children

Finally it is worth raising the issue of folate again. mike originally asked whether the data from the Gambia on folate inhibiting fansidar was a real problem-especially again in the setting in camps where children may all be getting it. With fitsum Assefa we set out to re examine this. For various reasons it has taken longer than expected but the emerging picture is rather different from what we had first thought--it does infact look as if even low dose folate ( 400 micrograms a day) produces a significant increase in drug failure, which in a situation where resistance is emerging rapidly is potentially a problem. i have no answer to this except to say again that it adds more to the argument for establishing a proper diagnoses. in children being treated for malaria where we don't think folate deficiency is a big issue but who are none the less aanemic ( the majority of kids we see in clinic) we adopt a fudge and delay folate for a week-but i guess thats not so practical for those where folate deficiency is a real problem.

Sorry, this has gone on much longer than intended and i suspect the usefulness to length ratio is rather poor--but its a real problem area. i have forwarded this to Bill Watkins who i dont think receives the NGONut broadcasts--he is a fundi on fansidar and may also want to add in information on how people can obtain up to date local information on resistance patterns

 

kevin marsh


Date: Sat, 13 Feb 1999 09:05:14
From: Tony Nelson <tony-nelsonatcuhk.edu.hk>
Subject: Ngonut: Malaria and Malnutrition

 

In response to the question of malaria treatment in malnourished kids,
Kevin Marsh notes that in his experience malnutrition does not protect
against severe malaria-and in fact is a risk factor for it. He notes that
this is not necessarily incompatible with some of the famous/notorious
studies in the literature ...

My understanding is that there is reasonable evidence that compared to
malnourished children, well nourished children have more severe malaria
(1,2,3) Hendrickse observed significantly higher levels of parasitaemias,
occurrence of convulsions and cerebral malaria in well nourished African
children compared to their malnourished counterparts (1). A strong
correlation between weight-for-age and levels of parasitaemia has also been
reported in Indian children. (4) Along a similar trend, an upsurge in
malarial incidence with re-feeding in refugee camps has been
documented.(5,6,7) In addition, the more poorly nourished children in these
camps were found to have a lower probability of developing high
parasitaemias compared the to the relatively better nourished ones.(7)
These epidemiological findings are supported by in vitro work demonstrating
a role for various nutritional agents in modulating malaria infection.(3,8)

My previous clinical experience also supported this observation that
malnutrished children appear to get malaria once their nutritional state
improves. I am interested to know why kevin marsh considers these studies
to be "notorious" and whether he has references to show that malnutrition
is a risk factor for malaria.


Tony Nelson

References

1. Hendrickse RG, Sherman PM. Malaria in early childhood. An investigation
of 500 seriously ill children in whom a "clinical" diagnosis of malaria was
made on admission to the children's emergency room at University College
Hospital Ibadan. Ann Trop Med Parasitol 1971;65:1-20.
2. Edirinsinghe JS. Infections in the malnourished with special reference
to malaria and malnutrition in the tropics. Ann Trop Paed 1986;6:233-7.
3. Oppenheimer SJ. Interactions of Malaria with Nutrition. Hong Kong J Paed
1992;1:5-14.
4. Ahmad SH, Moonis R, Shahab T, Khan HM, Jilani T. Effect of nutritional
status on total parasite count in malaria. Indian J Paed 1985;52:285-8.
5. Murray MJ, Murray AB, Murray MB, Murray CJ. Somali food shelters in the
Ogaden famine and their impact on health. Lancet 1976;i:1283-5.
6. Murray MJ, Murray AB. Starvation's suppression and refeeding activation
of infection. An ecological necessity? Lancet 1977;i:123-5.
7. Murray MJ, Murray AB, Murray NJ, Murray MB. Diet and cerebral malaria:
the effect of famine and refeeding. Am J Clin Nutr 1978;31:57-61.
8. Senok AC, Nelson EAS, Li K, Oppenheimer SJ. Thalassaemia trait, red cell
age and oxidant stress: Effects on Plasmodium falciparum growth and
sensitivity to artemisinin. Trans R Soc Trop Med Hyg 1997:91:585-89.


Date: Wed, 17 Feb 1999 17:41:20 +0000

From: Kevin Marsh" <kmarshatafricaonline.co.ke>

Subject:

 

tony nelson very reasonably asks for more details on why I think undernutrition is a risk factor for malaria. i hope he won't feel I am slipping out of it if i give a ( relatively) brief response here and a fuller response when we publish some data later in the year ( I hope!).

First he asks why i used the word notorious ( i rather wish i had not!) -i used it because the story of undernutrition protecting against malaria is always trotted out , and the same references quoted, as if it were well founded fact - whereas a critical review of the literature, such as it is, leaves more questions than answers. Our starting point was wondering whether there was not a bit of a contradiction between the ideas that undernutrition and malaria are both massive determinants of childhood mortality but that one protects against the other. We were also struck that in the hospital we work in, where it seems pretty rare to see a well nourished child(!), there was no shortage of severe malaria ( indeed, thats why we are here).

We conducted a large case control study looking at a wide range of host, parasite and environmental factors that had been proposed to have an effect on susceptibility to malaria. the study had a quad design ie each case of severe disease was matched to a case of none severe malaria presenting at the same time and each clinical case ( severe and none severe) was matched on age and location to a community control. A total of 2128 children were recruited. In the 1063 well children in the community there was a significant inverse relationship with MUAC at all ages and the same held for parasite density ie the worst nourished tertile had significantly higher parsite densities than the middle , who in turn had higher densities than the best nourished tertile. I should stress that i don't attach a lot of weight to this as parasite density and rate have only a very distant relationship to malarial morbidity--i mention them because they are the opposite of what might have been expected.

We were much more interested in the clinical data- here overall nutritional status, whether measured by MUAC ( adjusted for age) or wt for age or weight for height showed a consistent relationship for severe malaria overall and for both severe malarial anaemia and cerebral malaria (strictly defined) such that the worse nourished tertile of the population had significantly greater risk.

how can one tie this in with the dogma? first the amount of clinical data on which the dogma is based is small and also refers to several quite distinct settings. The work from Ibadan was very important in trying to define the spectrum of malaria (they found that only 184 of their 500 "malaria" cases had parasites)..but it completely lacks epidemiological context ie the data on relationship betweeen weight (only available in 60% of the parasite positive children)and parasite densities and convulsions is simply given in tabular form for children using the hospital- there is no information on where they came from, though people i have asked who worked at ibadan at the time and since tell me that kids came from a whole range of environmental and socioeconomic backgrounds to the hospital.. Alternative explanations for a relationship between malaria and better nutrition that one would want to consider are that the better nourished children lived in a "better" part of the city and were exposed to less malaria --or were more likely to receive treatment or prophylaxis --and therefore were less immune.Of course I do not know whether there are, in fact, confounders hidden in this data from 30 years ago-but one would clearly try to take a whole set of factors into account when designing the study today. this is not a critiscism of the study-which was an important one from a clinical point of view-but i think one has to be very cautious in drawing any strong conclusions of an epidemiological nature.

The other kinds of clinical study referred to largely involve refeeding--these are absolutely fascinating and i guess well known to most Ngonut readers. i think one has to take these as they stand- and my interprettation, as i said in the first mail, is that there may be extremes of malnutrition at which the parasite really is held back by the absence of a particular nutrient, which when supplied allows it to take off..however, it may not be well founded to extend from this an argument that undernutrition in gerneral is good for you from a malaria point of view --indeed from the data i have summarised above it clearly is not if you are a child growing up in coastal kenya.

One of the things which really struck me as a non nutritionist is how often people have seemed quite happy to talk about severe deficiency of single nutrients in animal experiments and overall undernutrition in children in the same breath -and yet the relationship between nutritional status as measured by the standard general indices and any one specific nutrient is often tenuous--this was clear in or own studies referred to above where we also measured red cell folate and riboflavin status ( as both have been suggested to affect suceptibility to malaria). Folate had no relationship to risk of severe disease but neither did it to other measurements of nutritional status. Riboflavin was very interesting, deficiency was associated with a 2-3 times increased risk of severe malarial anaemia but was assocaited with a similar degree of protection against cerebral malaria. So for those who want it- there is evidence that being undernourished is good for you. ( though there was no correlation between riboflavin status and MUAC or wt for age or height).

my conclusion at the end of all this is that the relationship betwen nutritional status and risk of malaria is likely to be complex (no prizes for original thought there). There may well be specific nutrients that when severely deficient, do reduce risk of disease ( or in the case of ribflavin reduce chances of one manifestation while increasing the chances of another) but that for most of us the more important observation is that when compared with well matched community members undernutrition, as measured by the usual general indices, is assocaited with increased risk of severe malaria (just as it is is with other major infections that kill these children).

Of course i do not expect any one to take this on trust without access to the actual data-anymore than i would put too much weight on anyone elses anecdotal clinical impressions. I am embarassed that it has taken so long to get round to getting the data out and i have only mentioned it now because i have been asked to. hopefully this will be the spur needed to finally get the damn stuff published!

 

Kevin Marsh


Date: Wed, 17 Feb 1999 16:37:47 -0500

From: "Dr. Nevin Scrimshaw" <nevinatcyberportal.net>

Organization: UNUCPO

Subject: Ngonut: (Nutrition and Malaria - Synergism and Antagonism

 

I appreciated Kevin Marsha's comment on "Malaria and Malnutrition" and found them sensible and convincing. His point that people quote experimental studies in animals as if they apply to malnourished human population is well taken. In the 1968 WHO Monograph on "Interactions of Nutrition and Infection" that I wrote with Carl Taylor and John Gordon, we introduced the concepts of synergist and antagonism between nutrientr deficiencies and infection.

In an exhuastive and critical review of the literature of the time, we found that it was possible to produce a deficienciency of almost any specific nutrient sufficiently severe as to inhibit infection, that we labelled antogonism. There were many studies of severe deficiencies of specific B-vitamins in animals sufficient to inhibit viral replication. In many cases metabolic antagonists were given to increase the severity of the deficiency. Later on excellent study of Baggs and Miller showed that morbidity and mortality increased progressively in rats with increasing iron deficiency in the diet until at zero iron intake, morbidy and mortality suddenly returned to levels associated with adequate iron intake. Noteworthy is that it took a zero iron intake to produced antagonisms. At lesser levels of iron deficiiency the immune system was so damaged that the relatonship wasone of synergism. The Murray papers of exacerbation of cerebral malaria in Somalia refugees with treatment of the anemia at been published at the time of the monograph and seemed plausible. Similarly, a paper by MacFarland reported that children with Kwashiorkor given parenteral iron therapy of their anemia had overwhelming infections and a high mortality. This too was plausbile that a sudden infusion of iron in children with severely compromised immunity due to protein deficiency would be at the mercy of pathogenic organisms when the capacity to withhold iron from invading organisms was overwhelmed by iron therapy.

HOWEVER, WE WERE UNABLE TO FIND ANY EXAMPLES WHERE THE DEFICIIENCY WAS SEVERE ENOUGH AND SPECIFIC ENOUGH IN THE NORMALLY MALNOURISHED POPULATIONS OF DEVELOPING COUNTRIES AS TO PRODUCED ANTAGONISM INSTEAD OF SYNERGISM.

There were some studies then and many more since showing that nutiional improvement reduces morbidity from infections, including supplementation with 60 mg. or iron.

The combination oif protein malnutrition and malaria results in synergism unless very severe then it is associated experimentally with antagonism in chickens, rats, mice and monkeys (See monograph page 84). .

The following may be of interest:

Excerpt from: Scrimshaw, N.S. Keynote Address: Functional significance of iron deficiency. In: Functional Significance of Iron Deficiency - Third Annual Nutrition Workshop. Enwonwu, C.(ed.). Nashville: Meharry Medical College; 1990: 1-14.

"It is not only the host that needs iron for the biochemical functions mentioned in the introduction, but also the infectious agent (66). Without it replication is inhibited. In fact, withholding iron from the infectious agent appears to be an important resistance mechanism of resistance to infections (67, 68). Conalbumin and lactoferrin have stronger iron binding properties than most bacterial siderophores and are normally highly unsaturated and function as iron-withholding rather than iron-transport agents.

Lactoferrin, known to be released upon degranulation of leucocytes in aseptic areas, is a major component of human milk and resists proteolytic destruction in the gastrointestinal tract. It is not difficult to demonstrate in vitro the protective effect of lactoferrin in vitro (69). In the iron- deficient host with reduced cell mediated immunity and leukocyte function, lack of available iron for agent replication is protective. Baggs and Miller (24) found that in rats exposed to a standard dose of Salmonella, a diet lacking in iron is almost as protective as one meeting iron needs.

Murray and Murray have described the exacerbation of malaria with a high case fatality rate in Somalia refugees given therapeutic doses of iron (70, 71). Parenteral iron given to children with kwashiorkor has also been associated with mortality from overwhelming infection (72, 73). However, in our supplementation studies in Egypt (29) and Indonesia (31) morbidity from diarrheal and respiratory disease decreased promptly with iron supplementation. The iron supplement promoted recovery of immune function without providing enough iron to increase the severity of existing or subsequent infections."

 

24. Baggs RB, Miller SA. Nutritional iron deficiency as a determinant of host resistance in the rat. J Nutr 103: 1554-1560, 1973.

71. Murray MJ, Murray AB, Murray BA, Murray MB. Diet and cerebral malaria: The effect of famine and refeeding. Am J Clin Nutr 31:57-61, 1978.

72. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J 2: 1113-1115, 1978.

73. McFarlane HS, Reddy KJ, Adcock, Adeshina H, AR Cooke and J. Akene. Immunity, transferrin and survival in Kwashiorkor. Br Med J 4: 268-270, 1970.