(C) Our World in Data
This story was originally published by Our World in Data and is unaltered.
 . . . . . . . . . .



Burden of Infection on Growth Failure [1]

['Stephensen', 'Charles B.', 'U.S. Department Of Agriculture Western Human Nutrition Research Center', 'Uc Davis Department Of Nutrition', 'University Of California', 'Davis']

Date: 1999-02-01  

Abstract

The high prevalence of infections among children living in poor areas of developing countries impairs linear growth in these populations. Acute, invasive infections, which provoke a systemic response (e.g., dysentery and pneumonia), and chronic infections, which affect the host over a sustained period (e.g., gut helminth infections), have a substantial effect on linear growth. Such infections can diminish linear growth by affecting nutritional status. This occurs because infections may decrease food intake, impair nutrient absorption, cause direct nutrient losses, increase metabolic requirements or catabolic losses of nutrients and, possibly, impair transport of nutrients to target tissues. In addition, induction of the acute phase response and production of proinflammatory cytokines may directly affect the process of bone remodeling that is required for long bone growth. Infection of cells directly involved in bone remodeling (osteoclasts or osteoblasts) by specific viruses may also directly affect linear growth. Many interventions are possible to diminish the effect of infection on growth. Prevention of disease through sanitation, vector control, promotion of breast-feeding and vaccination is crucial. Appropriate treatment of infections (e.g., antibiotics for pneumonia) as well as supportive nutritional therapy (again including breast-feeding) during and after recovery, is also important. Targeted therapeutic interventions to decrease the prevalence of gut helminth infections may also be appropriate in areas in which such infections are widespread. Such interventions are of public health benefit not only because they reduce the incidence or severity of infections, but also because they decrease the long-term detrimental effect of malnutrition on populations.

Infectious diseases of childhood are a crucial public health problem in developing countries and have long been known to affect growth. This is particularly true in poor areas of developing countries in which the incidence of infection can be quite high. In such settings, sanitation is often poor, leading to an increased incidence of infections transmitted by the fecal-oral route (e.g., diarrhea and some intestinal helminth infections). Vaccine coverage may also be incomplete in such communities, leading to a high incidence of vaccine-preventable diseases such as measles. Finally, diagnostic, curative and supportive care (inpatient, outpatient or at home) for sick children may also be less than adequate, leading to longer duration or increased severity of some infections such as lower respiratory tract infections. In addition, malnutrition may also be prevalent among children in these communities and can lead to increased severity or duration of infection.

This paper will briefly consider the following three questions related to the effect of infection on the linear growth of children who grow up in such settings. 1) Do infections affect linear growth and, if so, which infections have the largest impact? 2) How do infections affect linear growth? The answer to this question will focus primarily on the detrimental effect of infection on nutritional status but will also consider the possibility that certain infections may affect the physiologic processes of linear growth more directly. 3)Which public health interventions can diminish the impact of infection on linear growth?

IMPACT OF INFECTION ON LINEAR GROWTH

Most studies among young children in developing country settings have documented the effect of infection on weight gain. A particularly good illustration of the impact of repeated infections on weight gain for an individual child is seen in Figure 1.This figure illustrates both the high incidence of infection, particularly after weaning at ∼6 mo of age, and the association of these episodes of infection with weight loss. Many of the episodes of infection associated with weight loss in Figure 1 were due to diarrheal pathogens. The high frequency of infection also prevents catch-up growth, which could otherwise occur and allow the child to regain his or her expected growth trajectory.

FIGURE 1 Open in new tabDownload slide Association of repeated episodes of infection on weight gain in a Guatemalan child during the first 3 y of life. Adequate growth was seen during periods of exclusive breast-feeding and subsequent weight loss was associated with periods of infection. (Reproduced, with permission, from Mata 1992.)

Documenting the association of infections with decreased growth is more difficult for linear growth than it is for weight gain for at least two reasons. First, height (or recumbent length) does not decrease, as does weight. Second, longer time intervals are required to document linear growth (months) than are needed for changes in weight (days or weeks). However, such associations have been seen in many community studies around the world. For example, a community-based, longitudinal study of rural Guatemalan children <7 y of age showed that children with a high prevalence of diarrhea had slower linear growth than did children with a lower prevalence of diarrhea (Martorell et al. 1975). All diarrheal pathogens do not have the same impact on growth, however. A longitudinal, 1-y community surveillance of infants enrolled at birth in The Gambia showed that while an infant was suffering from diarrhea, ∼1 mm of length per week was lost compared with his or her own growth rate during diarrhea-free periods (Rowland et al. 1977). A similar study in rural Bangladesh revealed that a child without diarrhea would gain, on average, 0.42 cm more per year than would a child with the average prevalence of diarrhea (13% of days) (Black et al. 1984). More specifically, Shigella infection (which causes dysentery, an invasive diarrheal disease) was significantly associated with impaired linear growth, whereas infection with enterotoxigenic Escherichia coli or rotavirus (both of which cause watery diarrhea) was not associated with such deficits. In Brazil, hospitalization for either diarrhea or pneumonia during a 2-y period was associated with diminished linear growth (as judge by changes in height-for-age Z-scores) over that period of time (Victora et al. 1990). The relative effect of diarrhea (-1.11 sd for children hospitalized with diarrhea compared with -0.64 sd for those not hospitalized with diarrhea; P < 0.001) was somewhat greater than was that of pneumonia (-0.87 sd for children hospitalized with pneumonia compared with -0.66 sd for those not hospitalized with pneumonia; P < 0.001) in this analysis. Thus, serious acute infections, particularly those that involve the gastrointestinal tract, impair linear growth.

Chronic infections can also impair linear growth. Such infections may be subclinical and thus asymptomatic from the viewpoint of the patient or clinician. However, the cumulative effect of such infections may be substantial if the appropriate indicator is examined. For example, infection with Ascaris lumbricoides and other gut helminths may not produce obvious symptoms of disease but can nonetheless impair linear growth (Hlaing 1993, Stephenson 1987). Early infection with human immunodeficiency virus (HIV)2may also be asymptomatic; however, in a 6-y longitudinal study of the growth of 109 infants born to HIV-infected mothers, infants who were infected perinatally with HIV (n = 59) had impaired linear growth by 15 mo of age (compared with the 50 uninfected subjects) and eventually had a height deficit of ∼8 cm (Saavedra et al. 1995). Opportunistic infections may have accounted for diminished growth in some, but not all, children. Helicobacter pylori can cause a chronic bacterial infection of the stomach and duodenum and, in some cases, can cause gastric or duodenal ulcer disease. In a cross-sectional study of 4742 randomly selected subjects 12–64 y of age in Northern Ireland, past H. pylori infection (diagnosed with serum antibody) was found to be associated with shorter attained height in adult women (-0.8 cm, P < 0.05) and men (-0.6 cm, P < 0.05) after adjustment for other variables (Murray et al. 1997). Similar observations have also been made in Italian children (Perri et al. 1997). Although it has not yet been demonstrated that this association is causal, these results imply that linear growth retardation by infectious diseases is not limited to poor children living in developing countries.

IMPACT OF INFECTION ON NUTRITIONAL STATUS

Acute and chronic infections may impair linear growth by causing micronutrient malnutrition. For example, diarrhea, acute respiratory infections and chicken pox have all been associated with the development of vitamin A deficiency (Campos et al. 1987, Rahman et al. 1996, Sommer et al. 1987). Micronutrient deficiencies may be produced by infectious diseases in one of the following five ways: 1) decreasing food intake (anorexia); 2) impairing nutrient absorption; 3) causing direct micronutrient losses; 4) increasing metabolic requirements or catabolic losses; and 5) impairing transport to target tissues (although this has not been demonstrated conclusively).

Acute infections lead to decreased food intake, although breast-milk intake may be largely unaffected. The magnitude of the decreases is typically related to the severity of infection. Community studies in Guatemala have shown that children with acute respiratory infections or diarrhea consume ∼8 and 18% fewer total calories per day, respectively, than do children without these infections (Martorell et al. 1980). More severe infections can lead to much larger deficits in food intake. African children examined during the acute phase of measles consumed 75% fewer total calories than they did after recovery (Duggan et al. 1986). Interestingly, a community study from Peru has shown that breast-milk intake is not diminished by infection (Brown et al. 1990). Although total energy intake from non-breast–milk sources in a cohort of 131 Peruvian infants decreased by 20–30% when they had diarrhea or fever, no measurable decrease was seen in breast-milk intake. Thus the total deficit in calories was only 5–6% and was accounted for entirely by decreased intake of non-breast–milk foods.

Enteric infections such as diarrhea and gut helminth infections can lead directly to malabsorption of nutrients, but other infections may also impair absorption. Both acute diarrhea, caused by bacteria, viruses and protozoa, and chronic intestinal helminth infections (e.g., caused by A. lumbricoides) can damage intestinal mucosal epithelial cells and thus impair absorption of both macro- and micronutrients (Mata 1992, Stephenson 1987). The severity of the infection (as measured by the extent of tissue damage, volume of diarrhea or number of helminth ova per gram of stool) often predicts the magnitude of malabsorption. Even nonenteric infections may affect absorption, although the mechanism is unclear. For example, although uninfected children absorb 99% of a tracer dose of vitamin A, and children with diarrhea and Ascaris infection absorb 70 and 80%, respectively, children without apparent enteric infection who have pneumonia absorb only 74% of the dose (Sivakumar and Reddy 1972 and 1975,).

Even after nutrients are absorbed, they may still be lost as a result of infection with a number of pathogens that can cause direct nutrient loss, most commonly into the gut or urine. It appears that all febrile infections cause leakage of low-molecular-weight proteins into the urine. Although this phenomenon may cause some protein loss, one of the proteins lost may be retinol-binding protein (RBP), the serum transport protein for vitamin A. Thus vitamin A may be directly excreted into the urine with the losses increasing as the severity of infection increases (Stephensen et al. 1994). Direct tissue damage can also cause loss of nutrients in the urine. Egg production by adult pairs of Schistosoma haematobium living in the vesicular vein will lead to deposition of these eggs in the wall of the urinary bladder (as they make their way to the external environment; Stephenson 1987). Trapped eggs will cause granuloma formation in the wall of the bladder and will result in blood loss in the urine. A high intensity of infection will increase bladder damage and will lead to more blood loss. Perhaps the best known example of direct nutrient loss is the blood loss caused by hookworm infection (Stephenson 1987). These parasites directly damage the intestinal mucosa in order to derive nutrients for their own growth. The resulting blood loss can amount to several milliliters per day and can lead directly to the development of iron-deficiency anemia, with the severity of the anemia being directly proportional to the intensity of infection. Other enteric infections due to diarrheal pathogens can cause effusion of serous fluid into the gut, resulting in loss of serum proteins. This condition is exacerbated by measles virus infection and is called “protein-losing enteropathy” (Sarker et al. 1986).

Nutrient requirements may also be increased during infection. Although this has not been well documented for micronutrients, resting energy expenditure (REE) (and thus basal energy requirement) is increased. This phenomenon was recently documented in patients with HIV infection (Melchior et al. 1993). Subjects with asymptomatic HIV infection had a mean REE 16% greater than that of uninfected subjects, whereas HIV-infected subjects who also had opportunistic infections had a mean REE 57% greater than the control subjects. Infection, inflammation or increased oxidative stress may also increase catabolic loss of certain nutrients. For example, increased oxidative stress in the respiratory tract, particularly in smokers, is thought to lead to increased catabolic losses of folate (Heimburger 1992).

Finally, infection with most microorganisms leads to activation of macrophages and neutrophils by microbial products or by proinflammatory mediators (e.g., prostaglandins) produced by damaged cells. The release of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 results in induction of the systemic acute phase response (Baumann and Gauldie 1994). This response will lead directly to responses by the central nervous system (e.g., induction of fever and production of cortisol to down-regulate inflammation) and the liver, which includes the increased production of positively regulated acute phase proteins (e.g., C-reactive protein, or CRP) and the decreased synthesis of others, including RBP, which results in decreased serum retinol concentration. Serum iron and zinc concentrations are also decreased during the acute phase response. It is unclear whether these reductions in the serum micronutrient concentrations lead to decreased transport to target tissues. It has been suggested that chronic inflammatory diseases such as rheumatoid arthritis cause a mild, micro- to normocytic, hypochromic anemia termed the “anemia of chronic disease” (Walter et al. 1997). This seems plausible, but the cytokines produced during chronic inflammation may directly affect hematopoiesis and thus produce the anemia. It is also plausible that decreased serum retinol concentrations during infection could lead to decreased tissue concentrations of vitamin A, as recently discussed (Olson 1995); however, concrete data are lacking. Thus, the true effect of altered serum micronutrient concentration on the nutritional status of the host, or of specific tissues in the host, remains uncertain.

POSSIBLE DIRECT IMPACT OF INFECTION ON LINEAR GROWTH

Induction of the acute phase response and production of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 may directly affect the process of bone remodeling that is required for long bone growth. For example, osteoclasts are produced from the same myeloid precursor cell which, depending on the signals received, can also differentiate into monocytes. Although the network of cytokines and growth factors involved in the regulation of myeloid cell development is complex, increased production of TNF-α could lead to increased production of macrophages and diminished production of osteoclasts (Skerry 1994). The proinflammatory cytokines, particularly IL-6, may also directly affect osteoclast development and activity and may play a role in the pathologic bone loss seen in osteoporosis or in Paget′s disease, which is characterized in part by increased osteoclast activity (Barton 1997). IL-6 is also hypothesized to play a pathologic role in the impaired growth seen in children with inflammatory bowel disease. Malabsorption could play a role in this impaired growth but is apparently not the complete explanation because nutritional support does not fully restore normal growth. Experimental colitis in rats was induced as a model of inflammatory bowel disease and the effects on tibial growth plates were examined (Koniaris et al. 1997). A decrease in the proliferative zone was found compared with pair-fed control animals without colitis, and the extent of the decrease correlated with increased serum IL-6 concentrations. Thus, acute or chronic inflammation may modulate long bone growth via induction of IL-6 production.

Viral infection of osteoclasts or osteoblasts might also affect long bone growth. Osteoclasts can be infected with paramyxoviruses, such as the measles virus, and such infection may thus also play a role in bone loss, again including Paget′s disease (Shepard et al. 1996). It is also plausible that HIV, many strains of which infect macrophages, could infect osteoclasts and thus directly affect linear growth. Such a phenomenon could account for the observation in the cohort of infants infected perinatally with HIV (Saavedra et al. 1995) that linear growth was impaired at 15 mo of age, long before weight gain (weight-for-height) was affected (at 36 mo of age). Although this mechanism is speculative, it is clear that there are multiple pathways by which acute or chronic infections could directly modulate long bone growth.

INTERVENTIONS TO DIMINISH THE IMPACT OF INFECTION ON LINEAR GROWTH

What can be done today to minimize the effect of infection on linear growth? For all childhood infections, supportive therapy to minimize the severity of disease combined with nutritional support during and after infection to replace losses incurred during infections should help to maintain growth. Expansion of vaccine coverage to decrease the incidence of childhood diseases could also improve growth by decreasing the incidence of severe infections such as measles. Prevention of other frequent infections, such as diarrhea, through sanitation and vaccine development will also help to minimize the direct effect of infection on growth but will also allow catch-up growth to occur after episodes of infection by decreasing the high incidence of infection among young children in poor areas of developing countries (Guerrant et al. 1992). Promotion of breast-feeding will also decrease the morbidity from diarrhea and other infections, and will help maintain nutrient intake during infection (Brown et al. 1990). Targeted therapeutic interventions to decrease the incidence of gut helminth infections, such as Ascaris infection, have been shown to improve linear growth among children where such infections are prevalent (Hlaing 1993). Such selective chemotherapy, combined with improvements in sanitation to interrupt transmission, could well have significant benefits with regard to childhood growth.

In closing, it should be noted that all of these interventions can be justified on the grounds that they will decrease the total burden of disease during childhood. However, because such interventions will also decrease the incidence of stunting and wasting, they will also decrease the long-term (indeed, intergenerational) detrimental effect of malnutrition on populations. This point should be made to policy makers in the health field because it is important to understand that the benefit of improving nutritional status can be measured long after the immediate effect on the health of individual children has been assessed (Martorell 1995).

LITERATURE CITED

Barton , B. E. ( 1997 ) IL-6: insights into novel biological activities . Clin. Immunol. Immunopathol. 85 : 16 – 20 . Baumann , H. & Gauldie , J. ( 1994 ) The acute phase response . Immunol. Today 15 : 74 – 80 . Black , R. E. , Brown , K. H. & Becker , S. ( 1984 ) Effects of diarrhea associated with specific enteropathogens on the growth of children in rural Bangladesh . Pediatrics 73 : 799 – 805 . Brown , K. H. , Stallings , R. Y. , de Kanashiro , H. C. , Lopez de Romana , G. & Black , R. E. ( 1990 ) Effects of common illnesses on infants' energy intakes from breast milk and other foods during longitudinal community-based studies in Huascar (Lima), Peru . Am. J. Clin. Nutr. 52 : 1005 – 1013 . Campos , F. A. , Flores , H. & Underwood , B. A. ( 1987 ) Effect of an infection on vitamin A status of children as measured by the relative dose response (RDR) . Am. J. Clin. Nutr. 46 : 91 – 94 . Duggan , M. B. , Alwar , J. & Milner , R. D. ( 1986 ) The nutritional cost of measles in Africa . Arch. Dis. Child. 61 : 61 – 66 . Guerrant , R. L. , Schorling , J. B. , McAuliffe , J. F. & de Souza , M. A. ( 1992 ) Diarrhea as a cause and an effect of malnutrition: diarrhea prevents catch-up growth and malnutrition increases diarrhea frequency and duration . Am. J. Trop. Med. Hyg. 47 : 28 – 35 . Heimburger , D. C. ( 1992 ) Localized deficiencies of folic acid in aerodigestive tissues . Ann. N.Y. Acad. Sci. 669 : 87 – 96 . Hlaing , T. ( 1993 ) Ascariasis and childhood malnutrition . Parasitology 107 (suppl.): S125 – S136 . (suppl.): Koniaris , S. G. , Fisher , S. E. , Rubin , C. T. & Chawla , A. ( 1997 ) Experimental colitis impairs linear bone growth independent of nutritional factors . J. Pediatr. Gastroenterol. Nutr. 25 : 137 – 141 . Martorell , R. ( 1995 ) Results and implications of the INCAP follow-up study . J Nutr 125 (suppl.): 1127S – 1138 S. (suppl.):S. Martorell , R. , Habicht , J. P. , Yarbrough , C. , Lechtig , A. , Klein , R. E. & Western , K. A. ( 1975 ) Acute morbidity and physical growth in rural Guatemalan children . Am. J. Dis. Child. 129 : 1296 – 1301 . Martorell , R. , Yarbrough , C. , Yarbrough , S. & Klein , R. E. ( 1980 ) The impact of ordinary illnesses on the dietary intakes of malnourished children . Am. J. Clin. Nutr. 33 : 345 – 350 . Mata , L. ( 1992 ) Diarrheal disease as a cause of malnutrition . Am. J. Trop. Med. Hyg. 47 : 16 – 27 . Melchior , J. C. , Raguin , G. , Boulier , A. , Bouvet , E. , Rigaud , D. , Matheron , S. , Casalino , E. , Vilde , J. L. & Vachon , F. ( 1993 ) Resting energy expenditure in human immunodeficiency virus-infected patients: comparison between patients with and without secondary infections . Am. J. Clin. Nutr. 57 : 614 – 619 . Murray , L. J. , McCrum , E. E. , Evans , A. E. & Bamford , K. B. ( 1997 ) Epidemiology of Helicobacter pylori infection among 4742 randomly selected subjects from Northern Ireland . Int. J. Epidemiol. 26 : 880 – 887 . Olson , J. A. ( 1995 ) Vitamin A metabolism during infection . Kjolhede , C. Beisel , W. R. Vitamin A and the Immune Function: A Symposium The 1995 Haworth Medical Press New York, NY . eds. Perri , F. , Pastore , M. , Leandro , G. , Clemente , R. , Ghoos , Y. , Peeters , M. , Annese , V. , Quitadamo , M. , Latiano , A. , Rutgeerts , P. & Andriulli , A. ( 1997 ) Helicobacter pylori infection and growth delay in older children . Arch. Dis. Child. 77 : 46 – 49 . Rahman , M. M. , Mahalanabis , D. , Alvarez , J. O. , Wahed , M. A. , Islam , M. A. , Habte , D. & Khaled , M. A. ( 1996 ) Acute respiratory infections prevent improvement of vitamin A status in young infants supplemented with vitamin A . J. Nutr. 126 : 628 – 633 . Rowland , M. G. , Cole , T. J. & Whitehead , R. G. ( 1977 ) A quantitative study into the role of infection in determining nutritional status in Gambian village children . Br. J. Nutr. 37 : 441 – 450 . Saavedra , J. M. , Henderson , R. A. , Perman , J. A. , Hutton , N. , Livingston , R. A. & Yolken , R. H. ( 1996 ) Longitudinal assessment of growth in children born to mothers with human immunodeficiency virus infection . Arch. Pediatr. Adolesc. Med. 149 : 497 – 502 . Sarker , S. A. , Wahed , M. A. , Rahaman , M. M. , Alam , A. N. , Islam , A. & Jahan , F. ( 1986 ) Persistent protein losing enteropathy in post measles diarrhoea . Arch. Dis. Child. 61 : 739 – 743 . Shepard , S. L. , Cooper , R. J. & McClure , J. ( 1996 ) The effect on chick osteoclasts of infection with paramyxoviruses . J. Pathol. 179 : 448 – 452 . Sivakumar , B. & Reddy , V. ( 1972 ) Absorption of labelled vitamin A in children during infection . Br. J. Nutr. 27 : 299 – 304 . Sivakumar , B. & Reddy , V. ( 1975 ) Absorption of vitamin A in children with ascariasis . J. Trop. Med. Hyg. 78 : 114 – 115 . Skerry , T. M. ( 1994 ) The effects of the inflammatory response on bone growth . Eur. J. Clin. Nutr. 48 : S190 – S198 . Sommer , A. , Tarwotjo , I. & Katz , J. ( 1987 ) Increased risk of xerophthalmia following diarrhea and respiratory disease . Am. J. Clin. Nutr. 45 : 977 – 980 . Stephensen , C. B. , Alvarez , J. O. , Kohatsu , J. , Hardmeier , R. , Kennedy , J. I. , Jr & Gammon , R. B. , Jr ( 1994 ) Vitamin A is excreted in the urine during acute infection . Am. J. Clin. Nutr. 60 : 388 – 392 . Stephenson , L. S. ( 1987 ) Vitamin A is excreted in the urine during acute infection . Impact of Helminth Infections on Human Nutrition: Schistosomiasis and Soil-Transmitted Helminths Taylor and Francis Co New York, NY . Victora , C. G. , Barros , F. C. , Kirkwood , B. R. & Vaughan , J. P. ( 1990 ) Pneumonia, diarrhea, and growth in the first 4 y of life: a longitudinal study of 5914 urban Brazilian children . Am. J. Clin. Nutr. 52 : 391 – 396 . Walter , T. , Olivares , M. , Pizarro , F. & Munoz , C. ( 1997 ) Iron, anemia, and infection . Nutr. Rev. 55 : 111 – 124 .

Abbreviations

HIV human immunodeficiency virus

IL interleukin

RBP retinol-binding protein

REE resting energy expenditure

TNF tumor necrosis factor

© 1999 The American Society for Nutritional Sciences

[END]
---
[1] Url: https://academic.oup.com/jn/article/129/2/534S/4731689

Published and (C) by Our World in Data
Content appears here under this condition or license: Creative Commons BY.

via Magical.Fish Gopher News Feeds:
gopher://magical.fish/1/feeds/news/ourworldindata/