BACKGROUND Marasmus is one of the 3 forms of serious protein-energy malnutrition (PEM).

The other 2 forms are kwashiorkor (KW) and marasmic KW. These forms of serious PEM represent a group of pathologic conditions associated with a nutritional and energy deficit occurring mainly in young children from developing countries at the time of weaning. Marasmus is a condition primarily caused by a deficiency in calories and energy, whereas kwashiorkor indicates an associated protein deficiency, resulting in an edematous appearance. Marasmic kwashiorkor indicates that, in practice, separating these entities conclusively is difficult; this term indicates a condition that has features of both.[1, 2] These conditions are frequently associated with infections, mainly GI. The reasons for a progression of nutritional deficit into marasmus rather than kwashiorkor are unclear and cannot be solely explained by the composition of the deficient diet (ie, a diet deficient in energy for marasmus and a diet deficient in protein for kwashiorkor). The study of these phenomena is considerably limited by the lack of an appropriate animal model. Unfortunately, many authors combine these entities into one, thus precluding a better understanding of the differences between these clinical conditions. Marasmus is a serious worldwide problem that involves more than 50 million children younger than 5 years. According to the World Health Organization (WHO), 49% of the 10.4 million deaths occurring in children younger than 5 years in developing countries are associated with PEM. See the image below.

Malnutrition hotspot map. Image courtesy of the World Health Organization (WHO) and United Nations Children's Fund (UNICEF). Malnutrition has been a permanent priority of the WHO for decades. Although a higher proportion of severely malnourished children do not survive a significant intercurrent illness, as much as 80% of the overall, unacceptably high, mortality rate may be contributed by mild-to-moderately malnourished children because this cohort is so much higher.[3] Accordingly, newer strategies need not be limited to only severely malnourished children. Although PEM occurs more frequently in low-income countries, numerous children from higher-income countries are also affected, including children from large urban areas and of low socioeconomic status, children with chronic disease, and children who are institutionalized. Recently, studies of hospitalized children from developed countries have demonstrated an increased risk for PEM. Risk factors include a primary diagnosis of mental retardation, cystic fibrosis, malignancy, cardiovascular disease, end stage renal disease, oncologic disease, genetic disease, neurological disease, multiple diagnoses, PICU admission, or prolonged hospitalization.[4, 5] In these conditions, the challenging nutritional management is often overlooked and underestimated, resulting in an impairment of the chances for recovery and the worsening of an already precarious neurodevelopmental situation. PEM results in not only high mortality (even for hospitalized children), without any improvement over the last 2 decades, and also results in morbidity, stunted linear growth, and compromised neurological development. The social and economic implications of PEM and its complications are incalculable.

This article focuses mainly on marasmus that results from an insufficient nutritional intake as observed under impaired socioeconomic conditions, such as those present in developing countries. Marasmus is most frequently associated with acute infections (eg, gastroenteritis, respiratory illnesses, measles), chronic illnesses (eg, tuberculosis, HIV infection) or drastic natural or man made conditions (eg, floods, droughts, civil war). PATOFISIOLOGI Various extensive reviews of the pathophysiological processes resulting in marasmus are available. Unlike kwashiorkor, the clinical sequelae of marasmus can be considered as an evolving adaptation in a child facing an insufficient energy intake. Marasmus always results from a negative energy balance. The imbalance can result from a decreased energy intake, an increased loss of ingested calories (eg, emesis, diarrhea, burns), an increased energy expenditure, or combinations of these factors, such as is observed in acute or chronic diseases. Children adapt to an energy deficiency with a decrease in physical activity, lethargy, a decrease in basal energy metabolism, slowing of growth, and, finally, weight loss. Pathophysiological changes associated with nutritional and energy deficits can be described as (1) body composition changes, (2) metabolic changes, and (3) anatomic changes.

BODY COMPOSITION Body Composition

Body mass: Body mass is significantly decreased in a heterogeneous way. Fat mass: Fat stores can decrease to as low as 5% of the total body weight and can be macroscopically undetectable. The remaining fat is usually stored in the liver, giving a paradoxical appearance of a fatty liver. Although this is often observed in kwashiorkor, it also occurs to a lesser extent in marasmus. A study from Nigeria examined serum lipids in malnourished children.[6] These authors found that total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol levels were significantly higher in children with kwashiorkor than in those with marasmus. Total body water: The proportion of water content in the body increases with the increased seriousness of PEM (marasmus or kwashiorkor) and is associated with the loss of fat mass, which is poor in water. The proportion of extracellular water also increases, often resulting in edema. Edema is significant in kwashiorkor but can also be present in marasmus or in the frequently encountered mixed forms of PEM. The increase in extracellular water is proportional to the increase in the total body water. During the first days of therapy, part of the extracellular water shifts to the intracellular compartment and part of it is lost in the urine, resulting in the observed initial weight loss with treatment. Protein mass: Mainly represented by muscle and some organs (eg, heart), protein mass can decrease as much as 30% in the most serious forms. The muscle fibers are thin with loss of striation. Muscle cells are atrophic, and muscle tissue is infiltrated with fat and fibrous tissue. Total recovery is long but appears to be possible. Other organ mass: The brain, skeleton, and kidney are preserved, whereas the liver, heart, pancreas, and digestive tract are first affected.

Pediatric and adult physiologic change: Finally, physiologic changes are different in infants and children when compared with adults. For example, infants with marasmus have an increased tendency to hypothermia and hypoglycemia, requiring the frequent administration of small meals. This can be explained by the body composition imbalance of children with marasmus in favor of high-energyconsuming organs, such as the brain and kidney, compared with energystorage organs, such as muscle and fat. Assessment of fat and muscle mass: As described below, assessment of the fat and muscle mass loss can be clinically performed by measuring arm circumference (see image below) or skinfold thickness, such as triceps skinfold. The diagram illustrates the validity of this assessment method. Because arm circumference is relatively constant in healthy children aged 1-5 years, it roughly represents a general assessment of nutritional

status. Physiopathological principle of arm circumference measurement in children aged 1-5 years and the relationship with severity of malnutrition.

Potassium: Potassium is the electrolyte most studied in marasmus. Total body potassium deficit is associated with decreased muscle mass, poor intake, and digestive losses. This potassium deficit, which can reach 15 mEq/kg, contributes to hypotonia, apathy, and impaired cardiac function. Other electrolytes: Plasma sodium concentration is generally within the reference range, but it can be low, which is then a sign of a poor prognosis. However, intracellular sodium level is elevated in the brain, muscle, and red and white blood cells, explaining the sodium excretion in the first days of recovery. Other minerals: A deficit in calcium, phosphorus, and magnesium stores is also observed. Iron deficiency anemia is consistently observed in marasmus. However, in the most serious forms, iron accumulates in the liver, most likely because of the deficit in transport protein. These patients are at higher risk of mortality; therefore, iron is supplemented only after the acute recovery phase is completed. Zinc, selenium, and magnesium are more significantly reduced in kwashiorkor but are also constantly deficient in marasmus. Several studies have shown improved recovery from malnutrition and decreased mortality with supplementation of these 3 micronutrients. A Cochrane review concluded that zinc supplementation is clearly of benefit in children aged 6 months or older with diarrheal diseases in areas where these conditions are an important cause of childhood mortality.[7]

Vitamins: Both fat-soluble vitamins (ie, A, D, E, K) and water-soluble vitamins (eg, B-6, B-12, folic acid) must be systematically administered. Vitamin A is essential to retinal function, has a trophic effect on epithelial tissues, and plays a major role as an antioxidant agent. Vitamin A deficit affects visual function (eg, conjunctivitis, corneal ulcer, night blindness, total blindness) and digestive, respiratory, and urinary functions. Furthermore, vitamin A supplementation programs have resulted in decreased mortality and morbidity, in particular, during diarrheal disease and measles.

Mineral and vitamin Vitamin and micronutrient deficiencies can be differentiated in 2 categories listed below. Patients with deficiencies of type 1 nutrients present with late and specific clinical signs. In contrast, patients with deficiencies of type 2 nutrients are difficult to identify because blood levels are unreliable and the clinical signs are nonspecific, such as the growth retardation with mild deficiency and weight loss with significant deficiency. Furthermore, type 2 nutrient deficiencies are often combined. Therefore, these deficiencies are global and require a global nutritional rehabilitation, such as WHO standardized solution. Below are characteristics of type 1 and type 2 deficiencies, according to Golden from a 1991 report.

Type 1 deficiencies o Specific clinical signs o Clinical signs appear after a latency period o Used in specific metabolic pathways o Are independent of one another o Variable tissue concentration Type 2 deficiencies o Nonspecific clinical signs o Nutrient status related to daily intake o Used in various organs and metabolic pathways o Nutrient interaction o Constant tissue concentration

Below are lists of nutrient classification according to the clinical response to deficiency in type 1, with reduction of tissue concentration, and type 2 with growth deficit.

Type 1 nutrients o Selenium o Iodine o Iron o Copper o Calcium o Manganese o Thiamin o Riboflavin o Ascorbic acid o Retinol o Tocopherol

Calciferol Folic acid B-12 vitamin Pyridoxine Type 2 nutrients o Sodium o Sulfur o Essential amino acids o Potassium o Sodium o Magnesium o Zinc o Phosphorus o Water

o o o o

Metabolic Changes The overall metabolic adaptations that occur during marasmus are similar to those in starvation, which have been more extensively investigated. The primary goal is to preserve adequate energy to the brain and other vital organs in the face of a compromised supply. Early on, a rise in gluconeogenesis leads to a perceived increased metabolic rate. As fasting progresses, gluconeogenesis is suppressed to minimize muscle protein breakdown, and ketones derived from fat become the main fuel for the brain. With chronic underfeeding, the basal metabolic rate decreases. One of the main adaptations to longstanding energy deficiency is a decreased rate of linear growth, yielding permanent stunting. The energy saving is partially attenuated by the diversion of energy from muscle to the more metabolically active organs. Further adaptations to crisis situations, such as significant infections, may have some parallels to those that are observed in a stressed, malnourished animal model.[8] The rise in energy expenditure and urinary nitrogen excretion following surgery were significantly less in malnourished rats. This suggests that malnutrition can impair the ability of the organism to mobilize substrates to respond to stress. However, the healing process in these animals remained normal, indicating the ability to prioritize this biological activity.

Energy metabolism o With reduced energy intake, a decrease in physical activity occurs followed by a progressively slower rate of growth. Weight loss initially occurs due to a decrease in fat mass, and afterwards by a decrease in muscle mass, as clinically measured by changes in

arm circumference (see image below). Physiopathological principle of arm circumference measurement in children aged 1-5 years and the relationship with severity of malnutrition. o Muscle mass loss results in a decrease of energy expenditure. Reduced energy metabolism can impair the response of patients with marasmus to changes in environmental temperature, resulting in an increased risk of hypothermia. Furthermore, during infection, fever is reduced compared to a well-nourished patient. In case of nutrient deficiency, the metabolism is redirected to vital function (requiring 80-100 kcal/kg/d). During recovery, the energy cost of catch-up growth has to be added (up to 100 kcal/kg/d). At this stage, energy needs can be massive. Protein metabolism: Intestinal absorption of amino acids is maintained, despite the atrophy of the intestinal mucosa. Protein turnover is decreased (as much as 40% in severe forms), and protein-sparing mechanisms regulated by complex hormonal controls redirect amino acids to vital organs. Amino acids liberated from catabolism of muscle are recycled by the liver for the synthesis of essential proteins. Total plasma proteins, including albumin, are decreased, whereas gamma globulins are often increased by the associated infections. Albumin: An albumin concentration lower than 30 g/L is often considered as the threshold below which edema develops from decreased oncotic pressure. However, in marasmus, albumin concentration can occasionally be below this value without edema. Prealbumin concentration is a sensitive index of protein synthesis. It decreases with decreased protein intake and rapidly increases in a few days with appropriate nutritional rehabilitation. Insulinlike growth factor 1 (IGF-1) is another sensitive marker of nutritional status. Carbohydrate metabolism: This has mainly been studied in order to explain the serious and often fatal hypoglycemia that occurs in the initial renutrition phase of children with marasmus. The glucose level is often initially low, and the glycogen stores are depleted. Also, a certain degree of glucose intolerance of unclear etiology is observed, possibly associated with a peripheral resistance to insulin or with hypokalemia. In the initiation of renutrition or in association with diarrhea or infection, a significant risk of profound and even fatal hypoglycemia occurs. Small and frequent meals are recommended, including during the night, to avoid death in the early morning. Furthermore, the digestion of starch is impaired by the decreased production of pancreatic amylase. Lactose malabsorption is frequent but is generally without clinical consequences. In most cases, renutrition using milk is possible. Fat metabolism: Dietary fats are often malabsorbed in the initial phase of marasmus renutrition. The mobilization of fat stores for energy metabolism takes place under hormonal control by adrenaline and growth hormone. Blood lipid levels are usually low, and serious dysregulation of lipid metabolism can occur, mainly during kwashiorkor and rarely during marasmus.

Anatomic Changes Digestive tract The entire digestive tract from mouth to rectum is affected. The mucosal surface becomes smooth and thin, and secretory functions are impaired. A decrease in gastric hydrochloric acid (HCl) excretion and a slowing of peristalsis is observed, yielding bacterial overgrowth in the duodenum. Proportionally, the digestive tract is the organ system that loses the largest mass during marasmus. However, these important alterations of the digestive tract interfere only moderately with normal nutrient absorption. Therefore, early enteral renutrition is not contraindicated but is encouraged because some of the nutrients necessary for the recovery of the intestinal mucosa are used directly from the lumen. In addition to the anatomic changes associated with PEM, the frequent intestinal infections by viruses and bacteria and the toxins they produce also contribute to the changes in the digestive tract. Liver volume usually decreases, as do other organ volumes. An enlarged liver suggests the possibility of other diagnoses, such as kwashiorkor or hepatitis. Liver synthetic function is usually preserved, although protein synthesis is decreased, as reflected by the decreased albumin and prealbumin levels. Glycogen synthesis is decreased, further increasing the risk for hypoglycemia. The detoxifying function of the liver is impaired with structural changes in the liver cells. Therefore, drugs that are metabolized by the liver should be administered with caution, and liver function should be monitored. Endocrine system Many of the adaptations seen in marasmus are mediated by thyroid hormones, insulin, and growth hormone. As in any stressed state, the adrenergic response is activated (see image below).

Hormonal adaptation to the stress of malnutrition. The evolution of marasmus. This response is functional in marasmus but less so in kwashiorkor. Muscle proteins are converted into amino acids and are used for the hepatic synthesis of lipoproteins. These lipoproteins contribute to the mobilization of triglycerides from the liver. In contrast, during kwashiorkor, this function is impaired, resulting in liver steatosis, which is not usually present in marasmus. However, any precipitating factor, such as gastroenteritis or inappropriate renutrition, can disrupt this fragile adaptive mechanism. Furthermore, in serious marasmus, a significant degree of hypothyroidism, with a decrease in the size of the thyroid gland and repercussions on the brain function and psychomotor development exists. In less severe forms, the impaired thyroid function has fewer clinical consequences. Insulin levels are low and contribute to a certain degree of glucose intolerance, especially during kwashiorkor. Therefore, high-

carbohydrate diets are inappropriate. Growth hormone levels are initially within the reference range, but they progressively decrease with time, explaining the halt in linear growth observed with marasmus. After initiation of renutrition, the hormonal milieu is reversed allowing for substantial anabolism and a rapid linear growth spurt. However, if the marasmic state has gone on too long, then the adult height is less than the genetic potential. Recently, investigators have obtained data that suggest a role for additional hormones in PEM. Levels of serum gherlin(an appetite stimulating peptide) were increased[9] and serum levels of leptin (a satiety hormone) and IGF-1 were decreased in children with PEM compared with healthy controls.[10] Hematopoietic system A moderate normochromic or slightly hypochromic anemia is usually present, with normal RBC size. Iron and folate deficiencies, intestinal parasites, malaria, and other chronic infections exacerbate the anemia. However, iron stores are present in the liver. Therefore, iron supplementation should not be initially implemented. Oral iron is poorly tolerated by the digestive tract. The other blood cells (eg, thrombocytes, WBCs) are also affected, but with generally limited clinical consequences. Blood clotting mechanisms are usually preserved, except in the case of serious vitamin K deficiency. Immune system Immune impairment and infections are usually associated with marasmus. Thymus atrophy is a characteristic manifestation of marasmus, but all T lymphocyteproducing tissues are affected. However, B-lymphocyte tissues, such as Peyer patches, the spleen, and the tonsils, are relatively preserved. Cellular immunity is most affected, with a characteristic tuberculin anergy. However, antibody production is maintained. In marasmus, a general acquired immunodeficiency occurs, with a decrease in secretory immunoglobulin A (IgA) and an impairment of the nonspecific local defense system, such as mucosal integrity and lymphokine production. Bacteriemia, candidiasis, and Pneumocystis carinii infection are frequently present. Immune impairment is less frequent with moderate malnutrition. Immunological recovery is generally rapid, except if measles is associated. Brain and nervous system Cerebral tissue is usually preserved during marasmus. Brain atrophy with impairment of cerebral functions is only present in severe forms of marasmus. Effects on the brain are more important if malnutrition takes place during the first year of life or during fetal life. Irritability and apathy are characteristic of marasmus but improve rapidly with recovery. The permanent developmental consequences of marasmus are difficult to evaluate. Ongoing studies are evaluating these long-term consequences, as well as the benefit of nutritional supplementation with various vitamins and minerals. Cardiovascular system Cardiac muscle fiber is thin, and the contractility of the myofibrils is impaired. Cardiac output, especially systolic function, is decreased in the same proportion as the weight loss. Bradycardia and hypotension commonly occur in severe forms of malnutrition. Electrolyte imbalances present during marasmus modify the ECG findings. With this impaired cardiac function, any increase of intravascular volume during rehydration or blood transfusion can result in a significant cardiac insufficiency. With the rapid

metabolic, energy, and electrolyte changes of the initial phase of renutrition, this period is also a period of high risk for arrhythmia or cardiac arrest. Therefore, close clinical monitoring is critical in children with circulatory compromise. Epidemiology Frequency United States Marasmus is rarely reported in American children. In 1995, 228 deaths were attributed to marasmus in the United States. Most of these deaths were in elderly adults, and only 3 occurred in children. However, these data do not include deaths associated with marasmus complicating anorexia nervosa. Incidence of nonfatal marasmus is unclear in the United States because most patients have an underlying condition, and marasmus is not reported as an admission or discharge diagnosis. However, a report from a tertiary care center in Massachusetts reported prevalence rates of severe (1.3%), moderate (5.8%), and mild (17.4%) acute PEM in hospitalized children, based on the Waterlow criteria.[11] In the same cohort, chronic PEM (deficits in height for age) was found to be severe (5.1%), moderate (7.7%), and mild (14.5%). Acute (33%) and chronic (64%) malnutrition, based on comparing weight and height with controls, was found among a cohort of 160 children hospitalized with congenital heart disease in a regional pediatric cardiothoracic center at the University of Michigan.[12] Malnutrition was inversely correlated with age and was present in 80% of the hospitalized infants. These studies, as well as reports from Western Europe, suggest that marasmus is underappreciated amongst chronically ill children in the United States.[3, 4] International Nearly 30% of humans currently experience one or more of the multiple forms of malnutrition. Close to 50 million children younger than 5 years have PEM, and half of the children who die younger than 5 years are undernourished (see image below). Approximately 80% of these malnourished children live in Asia, 15% in Africa, and 5% in Latin America.[13]

Distribution of 10.4 million deaths among children younger than 5 years in all developing countries. World health Organization (WHO), 1995. Because as many as 20-30% of severely malnourished children die during treatment by the health services,[14] interest in reporting the prevalence of malnutrition in hospitalized children in different countries has been renewed. A recent review article estimated the prevalence of acute malnutrition

over the last 10 years in hospitalized children in Germany, France, the United Kingdom, and the United States to be 6.1-14%; the prevalence is as much as 32% in Turkey.[4] However, a recent German study determined that the prevalence of malnutrition was even higher (24% with 1.7% severe, 4.4% moderate, and 17.7% mild) in a cohort of unselected children admitted to a large tertiary care children's hospital in 2003-2004.[5] Furthermore, a worsening of nutritional status in hospitalized children in Brazil,[15] France,[16] and Turkey.[17] Paradoxically, a massive global epidemic of obesity, especially in countries in rapid economic transition, is simultaneously emerging in children and adolescents. Mortality/Morbidity Five million children younger than 5 years die every year of malnutrition. Approximately 70 million present with wasting, and 230 million present with some stunting. Fifty percent of the children in Asia are malnourished, 30% are malnourished in Africa, and 20% are malnourished in Latin America. Race No racial predilection in the prevalence of malnutrition is evident, but a strong association with the geographic distribution of poverty is observed. Sex No sexual predilection is observed, although, in some parts of the world, cultural practices place girls at a disadvantage for PEM. Age Marasmus is more frequent in children younger than 5 years because this period is characterized by increased energy needs and increased susceptibility to viral and bacterial infections. Weaning, which occurs during this period, is often complicated by factors such as geography (eg, drought, poor soil productivity), economy (eg, illiteracy, unemployment), hygiene (eg, access to quality water), public health (eg, number of nurses is more than number of physicians), and culture and dietetics (eg, intrafamily distribution of high-nutrition foods). A shrunken wasted appearance is the classic presentation of marasmus. Anthropometric measurements are critical to rapidly assess the type and severity of the malnutrition. The Wellcome Classification of Malnutrition in Children was generally used, but the WHO has revised this classification (see the table below). This simple classification allows a clear presentation of the clinical cases and allows comparisons between countries. Stunted children are usually considered to have a milder chronic form of malnutrition, but their condition can rapidly worsen with the onset of complications such as diarrhea, respiratory infection, or measles. Table 1. WHO Classification of Malnutrition (Open Table in a new window) Evidence of Malnutrition Moderate Severe (type)

Symmetric edema Weight for height

No

Yes (edema protein-energy malnutrition [PEM])* Standard deviation (SD) score SD score <-3 (ie, severe wasting) || (< 70%) -3 SD score <-2 (70-90%)

Height for age

SD

score-

3 SD score <-3 (ie, severe stunting) (< 85%)

SD score <-2 (85-89%) * This includes kwashiorkor (KW) and kwashiorkor marasmus (presence of edema always indicates serious PEM).

Standing height should be measured in children taller than 85 cm, and supine length should be measured in children shorter than 85 cm or in children who are too sick to stand. Generally, the supine length is considered to be 0.5 cm longer than the standing height; therefore, 0.5 cm should be deducted from the supine length measured in children taller than 85 cm who are too sick to stand.

Below the median National Center for Health Statistics (NCHS)/WHO reference: The SD score is defined as the deviation of the value for an individual from the median value of the reference population divided by the standard deviation of the reference population (ie, SD score = [observed value median reference value]/standard deviation of reference population).

This

is

the

percentage

of

the

median

NCHS/WHO

reference.

||

This corresponds to marasmus (without edema) in the Wellcome clinical classification and to grade III malnutrition in the Gomez system. However, to avoid confusion, the term severe wasting is preferred.

Construction and use of a wasting diagram simplifies the classification because the exact age of the child is often unknown. The wasting diagram is a large colored board made of vertical columns corresponding to weights from 2-25 kg (or 15 kg, which is often sufficient). The child is weighed and then his or her height is measured on the board in the column corresponding to the measured weight. The diagram is designed so that the height corresponds to the green zone if the child is well nourished, the yellow zone if the child is moderately malnourished, and to the red zone if the child is severely malnourished. Values within the reference range used to design this diagram can be applied to any population regardless of the racial origin. Middle upper arm circumference (MUAC) is a simple, low-cost, objective method of assessing nutritional status. The MUAC is generally as good as or better than other anthropometric measures in predicting subsequent mortality in community-based studies. It is also the most useful tool in large epidemiological surveys.

Physiopathological principle of arm circumference measurement in children aged 15 years and the relationship with severity of malnutrition. The most perceptible and frequent clinical feature in marasmus is the loss of muscle mass and subcutaneous fat mass. Some muscle groups, such as buttocks and upper limb muscles, are more frequently affected than others. Facial muscles are usually spared longer. Facial fat mass is the last to be lost, resulting, in severe cases, in the characteristic elderly appearance of children with marasmus. Anorexia is frequent and interferes with renutrition. An irritable and whining child who cannot be comforted or separated from the mother demonstrates behaviors often observed with marasmus. Apathy is a sign of serious forms of marasmus: children are increasingly motionless and seem to "let themselves die." In contrast, during rehabilitation, even the slightest smile is a positive sign of recovery. Children's behavior is probably one of the best clinical signs of the severity and evolution of marasmus. Several clinical signs must be assessed in order to detect complications, with special attention to infectious complications (see checklist below). The physical examination must be very thorough because even small abnormalities can be clinically significant. Clinical signs of serious complication can be very subtle in children with marasmus. A body temperature of 37.5C can correspond to a fever of 39-40C in a child without marasmus, and a small cough can be the only sign of a serious pneumonia. After history and physical examination, diagnosing the type and severity of the malnutrition, as well as diagnosing associated infections and complications affecting organs or systems, such as the GI, neurological, or cardiovascular system, are critical. This set of diagnoses results in optimal planning of the complementary evaluation and therapeutic strategy.

Checklist of points for conducting the physical examination o Body temperature (measured with a thermometer) - Allowing measurement of low temperatures to detect hypothermia as well as fever o Anemia - Pale mucosa o Edema o Dehydration - Thirst, shrunken eyes o Hypovolemic shock - Weak radial pulse, cold extremities, decreased consciousness o Tachypnea - Pneumonia, heart failure o Abdominal manifestations - Distension, decreased or metallic bowel sounds, large or small liver, blood or mucus in the stools o Ocular manifestations - Corneal lesions associated with vitamin A deficiency o Dermal manifestations - Evidence of infection, purpura o Ear, nose, and throat (ENT) findings - Otitis, rhinitis

Causes Several factors can lead to marasmus. Their relative importance varies between children and between parts of the world. For example, undernutrition associated with war, inappropriate weaning by a young mother, and precipitating infections can influence incidence of marasmus.

Nutrition: In many low-income countries, food variety is limited and results in mineral and vitamin insufficiencies. In cases of anorexia, which are generally associated with infection, the total energy intake becomes insufficient. Therefore, any nutrient deficiency can lead to marasmus because appropriate growth can only be ensured by a balanced diet. Therefore, marasmus can be described as multiple-deficiency malnutrition. Infections: Associated infections often trigger, aggravate, or combine with marasmus. However, evidence exists that this association may have been overestimated. For example, in rural Senegal, the growth of children with or without infections, such as pertussis and measles, was similar. In contrast, the importance of diarrhea in triggering malnutrition through anorexia and weight loss has been well established. Infectious diseases more frequently associated with energy-protein malnutrition are gastroenteritis, respiratory infections, measles, and pertussis. HIV also plays an increasingly significant role in some countries. Socioeconomic factors: Frequently, malnutrition appears during weaning, especially if weaning is suboptimal, as can occur with a low-variety diet, or if weaning foods are introduced only in children older than 8-10 months. The WHO recommends exclusive breastfeeding until age 6 months; then, the introduction of various additional foods is recommended. The socioeconomic environment is often critical in the choice of the weaning food used. For example, in northern Senegal, available foods are often limited to grains, vegetables, and a small amount of fish. Milk and meat are rare. In this region, malnutrition and diarrhea are frequent. In contrast, in the nearby Sahelien pastures where milk and meat are the main foods, diarrhea is less frequent, and malnutrition is rare. Other socioeconomic factors: Other factors, such as the famines associated with climatic disasters or more often with political events and war (as has been the case in east Africa), can play a critical role. The sociofamilial environment can also be important, and children of young or inexperienced mothers, twins, or female infants can be at a higher risk in some parts of the world. Summary: Marasmus, and malnutrition in general, represents multiple deficiencies, and multiple etiologies. Therefore, epidemiological, public health, and therapeutic approaches must be comprehensive. Population-based interventions limited to the supplementation of one nutrient have often been unsuccessful

Medical Care General objectives Management of moderate marasmus can be performed on an outpatient basis, but severe marasmus or marasmus complicated by a life-threatening condition generally requires inpatient treatment. In these

cases, management is divided into an initial intensive phase followed by a consolidation phase (rehabilitation), preparing for outpatient follow-up management. The WHO has developed guidelines to help improve the quality of hospital care for malnourished children and has prioritized the widespread implementation of these guidelines.

General Kwashiorkor.

principles

of severe

malnutrition

management. KW

The guidelines highlight 10 steps for routine management of children with malnutrition, as follows:[18]

Prevent and treat the following: o Hypoglycemia o Hypothermia o Dehydration o Electrolyte imbalance o Infection o Micronutrient deficiencies Provide special feeds for the following: o Initial stabilization o Catch-up growth o Provide loving care and stimulation o Prepare for follow-up after discharge

Because most patients with moderate cases of marasmus can be treated as outpatients, the optimal environment is a pediatric nutrition rehabilitation center. Nutritional rehabilitation should include appropriate foods for an intake up to 100-150 kcal/kg/d. Other therapeutic and preventive actions should include rehydration using the WHO solution (see below) in case of associated diarrhea, micronutrient supplementation (eg, iron, vitamin A), context-appropriate screening, and review of immunization status. This management should also incorporate nutritional and sociocultural education adapted to the local conditions. Family-based management is preferred with the child's mother as the key player. Nutritional management of the acute phase of severe marasmus (week 1) This period corresponds to maintenance of vital functions and tissue renewal (ie, maintenance needs). During this period, the electrolyte imbalance, infections, hypoglycemia, and hypothermia are treated, and then feeding is started. Oral renutrition of a child with marasmus should be started as early as

possible, as soon as the child is stable and the hydroelectrolyte imbalances are corrected. The term gut rest has no physiological basis. Enteral feeds decrease diarrhea and prevent bacteremia from bacterial translocation. Because of the instability of children with marasmus, clinical care must be well adapted, with grouping of patients, constant monitoring, and frequent clinical evaluation during the first days. Patients with marasmus should be isolated from other patients, especially children with infections. Treatment areas should be as warm as possible, and bathing should be avoided to limit hypothermia. Therefore, when possible, the hospital structure is best adapted for the treatment of severe malnutrition. In cases of shock, intravenous (IV) rehydration is recommended using a Ringer-lactate solution with 5% dextrose or a mixture of 0.9% sodium chloride with 5% dextrose. Enteral hydration using ReSoMal should be started as early as possible, preferably at the same time as the IV solution. The following rules should be implemented in the initial phase of rehydration: (1) use an nasogastric (NG) tube; (2) continue breastfeeding, except in case of shock or coma; and (3) start other food after 3-4 hours of rehydration. NG tube insertion is essential for both initial treatment (ie, rehydration, correction of electrolyte disturbances) and rehabilitation (ie, to provide the child the correct amount of diet every 2-4 h, day and night). The first step is often simply rehydration. Dehydration in children with marasmus is difficult to evaluate, is overdiagnosed, or is misinterpreted as septic shock. Rehydration should be enteral (by mouth or by NG tube) except in case of coma or shock, when intravenous therapy is required. For longer than two decades, the WHO had recommended that the standard formulation of glucosebased oral rehydration solution (ORS) should contain 90 mmol/L of sodium, 111 mmol/L of glucose, and a total osmolarity of 311 mmol/L. Numerous investigators have expressed concern about the concentration of sodium and glucose and investigated the feasibility of a reduced-osmolarity ORS. A Cochrane review from 2002 concluded that, in children admitted to the hospital with diarrhea, reduced osmolarity ORS (270 mmol/L) is associated with fewer unscheduled IV infusions, lower stool volume, and less vomiting than standard ORS.[19] Hyponatremia was not reported in these clinical studies. The authors note that in areas where cholera diarrhea remains a major problem, some clinicians may prefer to use the standard WHO formulation. The newer reduced-osmolarity ORS, which has been recommended by the WHO,[20] can be ordered as 1561120 - ORS, 1L sachet/Box-100 (instead of 1561110)or11561121-ORS,1Lsachet/Car-1000 (instead of 11561120). The ORS can be used for watery diarrhea, at the recommended volume of 5-15 mL/kg/h, with a total of 70 mL/kg for the first 12 hours. Because the risk of cardiac failure is increased in children with marasmus, compliance with the rehydration regimen is even more critical than in children who are well nourished. Therefore, closely monitor the rehydration phase and promptly address signs of cardiac failure, such as tachypnea, tachycardia, edema, or hepatomegaly. Rehydration solution should be adapted to marasmic children with a low sodium content and a high potassium content. This can be prepared using standard WHO solution as a base or by directly administering a modified oral rehydration (ReSoMal) solution if available. Table 2 highlights the composition of standard ORS, the new reduced-osmolarity ORS, and ReSoMal.

Table 2. Composition Comparison of ReSoMal, Standard WHO, and Reduced-Osmolarity WHO ORS Solutions (Open Table in a new window) Composition Glucose Sodium Potassium Chloride Citrate Magnesium Zinc Copper ReSoMal (mmol/L) Standard ORS (mmol/L) Reduced osmolarity ORS 125 45 40 70 7 3 0.3 0.045 111 90 20 80 10 ... ... ... 311 75 75 20 65 10 ... ... ... 245

Osmolarity (mOsm/L) 300

The overall goal of nutrition rehabilitation is to overcome the anorexia often associated with marasmus, as well as to avoid the causes that lead to anorexia. Another goal is to avoid cardiac failure while providing enough energy to avoid catabolism. The goal usually is to provide 80-100 kcal/kg/d in 12 meals per day or continuously by NG tube to avoid hypoglycemia. This amount of calories should be reached progressively in a few days to avoid life-threatening problems such as cardiac failure or hypokalemia. The WHO had recommended the use of the liquid products, such as the F75 solution, which provides 75 kcal/100 mL, mainly as carbohydrates. This solution provides a limited amount of fat, which is often malabsorbed because of the associated pancreatic insufficiency, and a limited amount of proteins, which can precipitate renal failure during initial refeeding of children with marasmus. F75 is available as a ready-to-use formula or can be prepared using widely available foods listed in Table 3 below. Recipes and cooking guidelines, including possible alternative foods, are available through the WHO. The readyto-use formulas, as well as the micronutrient mixtures, are commercially available. Table 3. Preparation of F75 and F100 Diets (WHO) (Open Table in a new window) Ingredient Amount in F75 Amount in F100 80 g 50 g

Dry skimmed milk 25 g Sugar 70 g

Cereal flour Vegetable oil Mineral mix Vitamin mix Water to mix

35 g 27 g 20 mL 140 mg 1000 mL

... 60 g 20 mL 140 mg 1000 mL

Rehabilitation phase (weeks 2-6) In the rehabilitation phase of treatment, nutritional intake can reach 200 kcal/kg/d. The goal is to reach a continuous catch-up growth in weight and height in order to restore a healthy body weight. Only children who have been weaned from their NG tube can be considered as being in the rehabilitation phase. Therefore, specific goals of this phase are as follows:

To encourage the child to eat as much as possible To restart breastfeeding as soon as possible To stimulate the emotional and physical development To actively prepare the child and mother to return to home and prevent recurrence of malnutrition

During the rehabilitation phase, the F100 formula, with a higher protein content (see Table 3 above) is recommended. With the child's increased appetite during this phase, use of the F75 formula only leads to a fat increase, without an appropriate gain in fat-free mass. The main risk of this phase of the rehabilitation is that the nutrients provided are not sufficient to sustain the weight gain, which can reach as much as 15 g/kg/d. Inexperienced health professionals often underestimate the needs of children with marasmus in this phase of nutritional rehabilitation. The increased iron needs associated with the rapid muscle growth and the hemoglobin increase justify iron supplementation starting in the second week of rehabilitation. Powdered skim milk is used to prepare the F75 or F100 formula. In that form, the lactose concentration is low, about 10 times less than in breast milk, which is also well tolerated by children with marasmus. Only in cases of persistent diarrhea or established lactose intolerance, which is rare, should lactose be excluded. High-fat foods are well tolerated at this point because they slow gastric emptying and may decrease lactose production. Plumpy'nut, a peanut-based paste with supplemental energy, vitamins, and minerals has been designed for malnourished children who are sufficiently well to benefit from outpatient care.[21] The WHO has recognized it as a ready-to-use-therapeutic food (RUTF) that can reverse malnutrition in severely malnourished children.[22] It was also successfully used by Doctors Without Borders in Niger in 2005. The paste is easy to eat, allowing children to feed themselves. The fortified peanut butterlike paste contains a balance of fats, carbohydrates, proteins, vitamins, and minerals. Peanuts themselves provide mono-unsaturated fats, which are easy to digest and are calorically dense, with ample amounts of zinc and protein. Because the product contains no water, it can last 2 years unopened.

A standard Plumpy'nut treatment for 4 weeks (2-3 times daily) costs 12 Euros in Africa. The cost of 4 weeks of Plumpy'nut and supplemental vitamin mixture (Unimix) is $35 per child. The cost in Haiti for a similar peanut butterbased product is slightly higher but still relatively inexpensive. The product can also be prepared locally in peanut-producing areas, such as Malawi and Niger, by mixing ground peanut and milk paste with a slurry of vitamins and minerals obtained from Nutriset, the French manufacturer of the paste. Emotional and physical stimulation is critical during this period. Psychomotor inhibition is evident in children with marasmus but rapidly improves with renutrition. Any rehabilitation practices that can minimize long-term developmental consequences should be implemented in children with marasmus. Practices available may vary depending on the environment. Practices include physiotherapy, sensory stimulation, and massages and should be implemented with or by the mother. Management of acute complications Mortality of hospitalized children with marasmus is high, especially during the first few days of rehabilitation. Death is usually caused by infections (ie, diarrhea and dehydration, pneumonia, gramnegative sepsis, malaria, urinary infection) or other causes (ie, heart failure associated with anemia, excess of rehydration solution, or excess of proteins in the first days of treatment; hypothermia; hypoglycemia; hypokalemia; hypophosphatemia). Mortality rates can vary from less than 5% to more than 50% of children, depending on the quality of care.

Infectious complications: Every hospitalized child with marasmus should be considered as having a bacterial infection. Treatment of bacterial infections prevents the development of septic shock, improves the response to nutritional rehabilitation, and decreases mortality. If the child has no clinical sign of infection, the WHO recommends 5 days of oral cotrimoxazole therapy. If the child presents with clinical signs of infection, hypoglycemia, or hypothermia (that does not rapidly respond to the kangaroo position), he or she must be considered as seriously infected and treated with parenteral ampicillin and gentamicin. If the child does not improve rapidly, chloramphenicol should be added. Antimalaria treatment is also indicated in endemic areas, either orally, by injection, or intrarectal. Other complications o Severe and symptomatic anemia (< 4 g/100 mL) with signs of heart failure should be treated with a blood transfusion of packed red cells to a maximum of 10 mL/kg administered over at least 3 hours. Cardiovascular tolerance should be closely monitored. The benefit of blood transfusion must be balanced with the risks of cardiovascular failure and the risk of infection (eg, hepatitis, HIV) associated with blood transfusion. [23] o Practice guidelines for acute diarrhea have been established. Persistent and profuse diarrhea has 2 main causes. Infectious etiology (especially lambliasis): This can be promptly treated with metronidazole if possible, after stool examination. Osmotic diarrhea: Sugar of the F75 solution should be replaced by cereal flour for 1-2 weeks. o Vitamin A deficiency is always present and should be treated in the first few days. Vitamin A replacement facilitates recovery from diarrhea, measles, and respiratory diseases and decreases the risk of blindness.

Lactose intolerance is unusual and often secondary to prolonged diarrhea. If, as dairy products are restarted, diarrhea persists despite antiparasitic treatment and nutritional rehabilitation, a transient lactose intolerance is possible, especially if stools have a low pH and if the child presents with a perianal skin inflammation (diaper rash). In case of lactose intolerance, milk should be withheld and yogurt or a commercially available lactose-free formula can be used.

Complications of the rehabilitation phase

Poor response to the nutritional rehabilitation: If the above recommendations are applied, children with marasmus should improve rapidly, gain weight regularly, and return to ageappropriate developmental status. Usually, poor response to treatment is due to insufficient intake or an underlying infection, especially HIV or tuberculosis. However, poor response to therapy requires a complete reassessment of the situation, rather than simply adding a medication or a micronutrient, which is usually ineffective. Psychosocial problems: Often during this period of the rehabilitation, underlying causes of the child's marasmus are understood, such as the previously described psychosocial factors. Changes in these underlying factors are often difficult because they are associated with the general socioeconomic conditions. However, changes should be attempted. The underlying factors should be taken into consideration when planning the child's return to home and further follow-up care.

Specific medical treatment regimens

In certain clinical scenarios, specific clinical routines that should be observed. In malnourished children with developmental disabilities, a systematic approach that was applied in a specialized feeding disorder clinic has been described.[24] Initially, specific deficits were identified. Diagnosis-specific treatment plans then resulted in significantly improved energy consumption and nutritional status. Consequently, the program decreased overall subsequent hospitalization rates and medical costs.

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