Rash with Diarrhea and Vomiting in a Healthy 13-month-old Boy

A previously healthy, fully vaccinated, 13-month-old boy presents to the emergency department (ED) with 4 weeks of a worsening rash, 1 week of subjective fevers and decreased appetite, and 2 days of nonbloody, nonbilious emesis with watery diarrhea. The rash began on the legs as red pruritic lesions that then spread to the abdomen 2 weeks before presentation. This was followed by involvement of the face and upper extremities, with “peeling” 3 days before presentation, although the palms and soles were spared. In addition to the rash, the patient’s mother reports bilateral swelling of the lower extremities and hands starting approximately 1 week before presentation, and facial swelling the morning of presentation. The mother denies eye puffiness and hair or nail changes.The patient’s mother denies any recent travel, known sick contacts, history of allergies, recorded fevers during illness, or exposure to new soaps, detergents, and foods. He takes no regular medications or vitamins, and he did not receive antipyretics at home. He did complete a 5-day course of amoxicillin for acute otitis media 5 weeks before presentation (although guidelines recommend a 10-day course for children <2 years old). The rash presented 2 days after completion of the antibiotics.He was born at term without complications, was an appropriate size for gestational age, and has been meeting all developmental milestones. Growth curves demonstrate an appropriate trajectory for head circumference (approximately 90th percentile) (Fig 1A) but a downward trend in length (from the 86th to the 33rd percentile) (Fig 1B) and weight (from the 82nd to the 28th percentile) (Fig 1C) starting from 6 months of age. Growth history before 6 months of age was unable to be obtained from the patient’s previous pediatrician. Nutritional history reveals that his diet consists primarily of hemp milk (30 oz/d), fruits, vegetables, and rice cereal. Further investigation reveals that he was breastfed until 3 months of age, when his mother transitioned to formula due to underproduction of breast milk, but noted intolerance and intermittent emesis, so instead transitioned to oat milk. On initial presentation of this rash at 12 months of age, she switched to hemp milk after the pediatrician suggested that the oat milk may be contributing to his rash. He has no other sources of dietary protein. He was evaluated by his pediatrician again for worsening rash 1 week before presentation, who prescribed topical mupirocin and triamcinolone, which did not help.In the ED, the patient is fussy but nontoxic and alert, with the following vital signs: temperature, 98.4°F (36.9°C); respiratory rate, 32 breaths/min; heart rate, 128 beats/min; blood pressure, 92/62 mm Hg; and oxygen saturation, 100%. His weight is 22 lb (10 kg, 55th percentile) and length is 28 in (71 cm, <3rd percentile).Skin examination (Fig 2) consists of a significantly desquamating, hyperpigmented, generalized rash sparing the scalp, palms, and soles. There are also scattered thin crusted monomorphic papules and patchy areas of hypopigmentation throughout. There are no erosions, bullae, eye or mucosal involvement, Koplik spots, or strawberry tongue. Hands and feet are notable for moderate edema. There is mild facial puffiness, with no periorbital swelling. Brittle, dry hair is noted. Nikolsky sign is negative. Cardiac examination reveals normal S1 and S2, no murmurs, and no S3 or S4 gallops. Lungs are clear to auscultation bilaterally. Abdomen is soft and nontender, without rebound. There is no hepatomegaly or palpable spleen tip. A complete blood cell count shows a white blood cell count of 8,900/µL (8.9 × 109/L) (reference range, 8,000–17,500/µL [8.0–17.5 × 109/L]) and is notable for a normocytic anemia with a hemoglobin level of 6.6 g/dL (66 g/L) (reference range, 11.3–12.5 g/dL [113–125 g/L]) and mean corpuscular volume of 78.9 µm3 (78.9 fL) (reference range, 70–86 µm3 [70–86 fL]). A basic metabolic profile is significant only for hyponatremia, with a sodium level of 130 mEq/L (130 mmol/L) (reference range, 135–145 mEq/L [135–145 mmol/L]). Liver function tests demonstrate hypoalbuminemia, with an albumin level of 2 g/dL (20 g/L) (reference range, 3.5–5.0 g/dL [35–50 g/L]) and a total protein level of 3.7 g/dL (37 g/L) (reference range, 6.0–8.0 g/dL [60–80 g/L]). Prealbumin level is 8.1 mg/dL (81 mg/L) (reference range, 15.0–30.0 mg/dL [150–300 mg/L]). Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin levels are normal. Coagulation studies show an elevated prothrombin time (PT) of 17.3 seconds (reference range, 11.8–14.8 seconds), with an international normalized ratio of 1.4 seconds (reference range, 0.9–1.2 seconds); activated partial thromboplastin time (APTT) is shortened at 25.8 seconds (reference range, 33.6–43.8 seconds).Iron studies show a serum iron level of 63 μg/dL (11.28 μmol/L) (reference range, 65–175 ng/mL [11.64–31.33 µg/L]), a ferritin level of 117 ng/mL (117 µg/L) (reference range, 25–270 ng/mL [25–270 µg/L]), total iron-binding capacity less than 63 μg/dL (<11.28 µmol/L) (reference range, 250–410 μg/dL [44.75–73.39 µmol/L]), and a transferrin level less than 50 mg/dL (<6.15 µmol/L) (reference range, 200–360 mg/dL [24.60–44.28 µmol/L]). Inflammatory markers are not elevated. Urinalysis from a bagged urine specimen is negative for protein, blood, nitrites, glucose, or bacteria and shows large leukocyte esterase with 6 to 10 white blood cells per high-power field. He is admitted to the general pediatrics team for further evaluation and management.This previously healthy patient presented with a subacute rash, edema, tactile fevers, diarrhea, and vomiting, with evidence of a normocytic anemia, hyponatremia, and severe hypoalbuminemia. Given the history and constellation of findings, etiologies are extensive and include infectious, allergic/immunologic, rheumatologic, gastrointestinal, nephrotic, neoplastic, and nutritional causes.Infectious etiologies on the differential diagnosis include staphylococcal scalded skin syndrome (SSSS), eczema herpeticum, multisystem inflammatory syndrome in children, and congenital syphilis. Patients with SSSS are usually toxic appearing with fever and diffuse pain, and the rash is characterized as generalized erythema with blisters and a positive Nikolsky sign. The absence of these findings makes SSSS unlikely. Eczema herpeticum may lead to worsening of his rash but is also unlikely with no history of eczema and no vesicles on examination. Multisystem inflammatory syndrome in children was considered due to the patient’s extensive rash and report of subjective fevers, but the patient’s COVID-19 antibodies were negative. Syphilis was low on the differential diagnosis because the patient exhibited no other common manifestations except for a rash (ie, no hepatomegaly, jaundice, lymphadenopathy, rhinitis). Furthermore, the rash in syphilis is typically maculopapular.Allergic/immunologic causes include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and serum sickness. SJS/TEN was considered due to the temporal relationship between antibiotic use and symptom onset, which is typically 4 days to 4 weeks after starting the offending medication. However, in SJS/TEN, the patient is toxic appearing, influenzalike symptoms typically precede the rash, and the rash is characterized as erythematous macules and purpura with acute onset and mucosal involvement. Serum sickness may present with fevers, rash, and painful joints, but it typically resolves once the causative agent is discontinued. Our patient received amoxicillin for acute otitis media 5 weeks before presentation, which does not fit the time course of this illness.Rheumatologic etiologies considered were Kawasaki disease (KD), Henoch-Schönlein purpura, and acute hemorrhagic edema of infancy. KD may present with a polymorphous rash and extremity swelling, as in our patient, but he lacked recorded fevers, conjunctivitis, lymphadenopathy, and a strawberry tongue. There was also no observed erythema of the palms and soles, which is common in KD. Finally, the absence of a purpuric rash makes Henoch-Schönlein purpura and acute hemorrhagic edema of infancy unlikely.Gastrointestinal etiologies were considered due to the patient’s hypoalbuminemia, diarrhea, and vomiting. The differential diagnosis includes protein-losing enteropathies such as celiac disease or inflammatory bowel disease. Hypoalbuminemia may also be caused by decreased albumin synthesis, as seen in liver dysfunction or protein malnutrition. Heart failure is very important to consider in patients with hypoalbuminemia and edema but is deemed less likely with a normal cardiopulmonary examination and no hepatomegaly. Nephrotic syndrome also causes hypoalbuminemia and edema; however, the patient’s urinalysis was negative for protein.We briefly considered Langerhans cell histiocytosis, which commonly presents as a rash with multisystem involvement including hypoproteinemia, but the rash is typically eczematous or papular. Furthermore, the patient did not have hypernatremia, diabetes insipidus, or lymphadenopathy commonly associated with Langerhans cell histiocytosis.Finally, given the patient’s hypoalbuminemia, hypoproteinemia, anemia, and limited diet, a malnutrition-related dermatitis was suspected, such as pellagra (niacin deficiency), acrodermatitis enteropathica (zinc deficiency), kwashiorkor (edematous protein malnutrition), or scurvy (vitamin C deficiency).The dietary history revealed that for the past 10 months, the patient’s diet consisted of oat milk and hemp milk as his only protein source, which contain 3 and 4 g of protein per 8 fl oz, respectively. The nutritional profiles of milk and select milk alternatives are summarized in the Table. (1)(2) Although the protein quantity in plant-based milk seems comparable with that of human milk or infant formula, plant proteins are deficient in certain amino acids (such as lysine), are less readily digestible, and, therefore, are of “lower nutritional quality.” (3)(4) This, in turn, may lead to protein malnutrition. Further evaluation revealed a low vitamin D level of 10.6 ng/mL (26.5 nmol/L) (reference range, 30–100 ng/mL [75–250 nmol/L]). Vitamins B12, C, and E; niacin; thiamine; and folic acid levels were normal. Zinc level was also normal, at 45 μg/dL (6.88 µmol/L) (reference range, 31–120 μg/dL [4.74–18.36 µmol/L]).The diagnosis of kwashiorkor was made given the patient’s significantly limited dietary protein intake in association with characteristic findings of severe hypoalbuminemia, diffuse edema, anemia, and desquamating dermatitis.Kwashiorkor is a type of severe protein-energy malnutrition, which is rare in developed countries and often found in resource-limited countries. Edema is a core clinical feature in kwashiorkor, which results from a multitude of mechanisms, including hypoalbuminemia, increased cortisol level, and decreased activation of antidiuretic hormone. (5) Other clinical features include dull or hypopigmented hair, rounded cheeks (“moon face”), distended abdomen, vomiting, diarrhea, and hepatomegaly from fat infiltration. (6)(7) Cutaneous findings may consist of hyperkeratotic or hyperpigmented skin progressing to erosions or desquamation, leading to a “flaky paint” or “peeling paint” appearance, (6)(8)(9) as seen in our patient.Cases in developed countries are primarily caused by parents with good intentions who substitute infant formula, cow milk, or human milk with low-protein alternatives in their child’s diet to help either true or perceived food intolerances. (7) Other etiologies may occur in the setting of chronic disease states that lead to increased energy expenditure, inadequate intake, or excessive gastrointestinal losses. (6)It is important to have a high index of suspicion for malnutrition in multisystem disease, even with apparently normal growth, because edema can mask muscle wasting. Prompt identification is crucial because malnourished patients are at significantly higher risk for developmental delays (10) and superimposed infection due to immune system dysregulation. (6)(11)Nutritional rehabilitation remains the cornerstone of treatment and management for kwashiorkor. Initial stabilization includes treating hypoglycemia, dehydration, electrolyte imbalances, and infection. (5)(6)(12)(13) An enteral feeding regimen should be implemented gradually with caloric restriction between 60% and 80% of caloric requirements (6) to reduce the risk of refeeding syndrome, in addition to empirical supplementation with thiamine and phosphate. Electrolytes should be monitored closely. Weight loss is expected due to resolving edema. Once stabilized, patients may need between 120% and 140% of their caloric requirement for weight recovery and growth. (6) In addition, deficiencies in specific micronutrients should be addressed and treated.For the skin lesions found in kwashiorkor, the World Health Organization recommends washing the affected areas in 0.01% potassium permanganate solution, applying barrier cream to the raw areas, and using gentian violet or nystatin cream on the sores. (12) Inpatient or outpatient management depends on clinical presentation. (13)The patient was admitted from the ED on acyclovir and clindamycin for possible infectious etiologies, with wound cultures and blood cultures pending. Dermatology, infectious disease, gastroenterology, and nutrition/dietary services were consulted. Acyclovir was discontinued once herpes simplex virus cultures were negative, but clindamycin was continued because wound cultures grew methicillin-susceptible Staphylococcus aureus, representing a likely superimposed bacterial skin infection. On thorough nutritional evaluation, management for kwashiorkor was initiated.The patient underwent a trial of an amino acid–based formula with a goal of 80 to 90 kcal/kg per day to achieve 90% of his estimated nutritional needs, and he was placed on a regular pediatric pureed diet. An intact protein formula was not started due to initial concern for a potential protein-losing enteropathy or protein allergy, with the reported history of previous intolerance to regular formula.He received supplementation with a multivitamin, vitamin D, thiamine, phosphate, and vitamin K. He required a packed red blood cell transfusion given worsening anemia on repeated complete blood cell count, which showed a decreasing hemoglobin level of 6.0 g/dL (60 g/L) (reference range, 11.3–12.5 g/dL [113–125 g/L]), although he was asymptomatic. The patient’s low total iron-binding capacity was thought to be due to low protein levels, and his mildly low iron level could suggest progression of his normocytic anemia to microcytic anemia.The patient received multiple doses of 25% albumin and furosemide with adequate response. His weight decreased from 22 lb (10 kg) to 19.6 lb (8.9 kg) by hospital day 9, likely due to resolving edema. A useful tool to assess nutritional status is the mid-upper arm circumference because weight may not always be accurate, but this was not performed during the hospitalization. Prealbumin level, which was low in this patient, may serve as a measure of recent protein intake but is a suboptimal marker of nutritional status due to confounding factors that affect its levels. (14)Celiac serologies and α1-antitrypsin levels, performed to assess for possible protein-losing enteropathy, were normal. Pancreatic elastase testing was also normal. Stool occult blood was negative. Abdominal ultrasonography to assess for liver abnormalities was performed because hypoalbuminemia may result from declining synthetic function of the liver, as seen in nonalcoholic steatohepatitis or other causes of cirrhosis, but no abnormalities were seen. In addition, we would expect an elevated PT and APTT in liver disease due to vitamin K deficiency, but the patient’s liver enzyme levels were normal and his coagulation studies do not reflect this to a significant degree. His prolonged PT and shortened APTT were thought to be due to poor sample collection or preparation and were not repeated. However, it is also possible that this patient may have been on the verge of developing zinc deficiency, which may present with a skin rash and early liver dysfunction, as indicated by the rising PT.Comprehensive metabolic panel was measured daily to monitor for refeeding syndrome. His sodium levels improved, and other electrolytes remained within normal limits. Albumin and protein levels also improved, with an albumin level of 3.3 g/dL (33 g/L) (reference range, 3.5–5.0 g/dL [35–50 g/L]) and a total protein level of 5.1 g/dL (51 g/L) (reference range, 6.0–8.0 g/dL [60–80 g/L]) before discharge. The patient’s rash and edema showed marked improvement, and clindamycin was transitioned to cephalexin before discharge. The patient did not receive antifungal testing or treatment due to his clinical improvement with antibiotics. His vomiting resolved, and stools became more formed. He was scheduled to follow up with gastroenterology and dermatology as an outpatient, but the family moved out of state after discharge. Phone call follow-up several months after hospitalization revealed that the patient is doing well. His mother reports that his rash and extremity swelling are completely resolved. He tolerates a well-varied diet with adequate intake of protein, including plant-based proteins (chickpeas, lentils, and beans) and soy milk. He is growing appropriately and continues to meet his developmental milestones.In evaluating a rash with multisystem involvement, nutritional deficiencies should be considered for prompt management and treatment.It is important to have a high index of suspicion for kwashiorkor in children who have concerning dietary histories despite normal-appearing growth and development, especially because edema may mask muscle wasting.Kwashiorkor can present with a specific rash, described as a “flaky paint dermatosis.”Nondairy beverages such at oat milk or hemp milk should not be used as substitutes for human milk, infant formula, or cow milk, especially in infants and children.Increased suspicion for nutrient deficiencies may be particularly critical in the United States with the shortage of infant formula at the time of this writing, which may unintentionally prompt well-meaning families to look to alternative methods to feed their children.