Cheng, Sam X.*; Bai, Harrison X.†; Gonzalez-Peralta, Regino*; Mistry, Pramod K.†; Gorelick, Fred S.†
*Department of Pediatrics, University of Florida, Gainesville
†Department of Pediatrics, Yale University, New Haven, Connecticut.
Address correspondence and reprint requests to Sam X. Cheng, MD, PhD, Department of Pediatrics, University of Florida, 1600 SW Archer Rd, RG-120, PO Box 100296, Gainesville, FL 32610 (e-mail: email@example.com).
Received 3 October, 2012
Accepted 7 January, 2013
The authors report no conflicts of interest.
ABSTRACT: Treatment of infectious diarrheas remains a challenge, particularly in immunocompromised patients in whom infections usually persist and resultant diarrhea is often severe and protracted. Children with infectious diarrhea who become dehydrated are normally treated with oral or intravenous rehydration therapy. Although rehydration therapy can replace the loss of fluid, it does not ameliorate diarrhea. Thus, during the last decades, there has been continuous effort to search for ways to safely stop diarrhea. Herein, we report 3 immunocompromised children who developed severe and/or protracted infectious diarrhea. Their diarrheas were successfully “halted” within 1 to 2 days following the administration of calcium.
Acute infectious diarrhea remains a potentially lethal worldwide problem, particularly in infants, young children, and immunocompromised patients (1,2). Although oral rehydration therapy is often used and is valuable for correcting dehydration, it does not “halt” the underlying intestinal fluid loss; its use in treating diarrhea has dropped significantly both by parents and practitioners (3). On the contrary, although there are a few antidiarrheal therapies available or in development (4), they are limited by their expense, lack of availability, and/or safety concerns. Thus, simple, safe, and inexpensive novel antidiarrheal therapies are needed. Based on our work on the role of calcium-sensing receptor (CaSR) (5–9), we assessed the effect of calcium supplementation to activate CaSR to treat infectious diarrhea in 3 immunocompromised children. Infectious diarrhea in these patients ceased within 1 to 2 days of oral/intravenous calcium administration.
AB is an 8-month-old boy with severe malnutrition and hypocalcemia who was referred for 2 weeks of worsening nonbloody watery diarrhea resulting from norovirus gastroenteritis that had been unresponsive to nil per os, intravenous bicarbonate, and rehydration therapy. His medical history was significant for Hirschsprung disease, intestinal lymphangiectasia, and feeding difficulty. Findings on the initial physical examination revealed a malnourished and thin child with tachycardia, tachypnea, dry mucus membrane, and a benign abdomen. His laboratory values and stool electrolyte analysis are shown in Table 1. Given the presence of severe hypocalcemia, he received daily intravenous calcium gluconate (1 mEq · kg−1 · day−1) replacement. Remarkably, as his serum ionized Ca2+ increased, his daily colostomy output decreased steadily (Fig. 1).
CD is a 13-year-old girl with pontine glioma receiving chemotherapy (irinotecan and avastin) complicated with cytomegalovirus colitis who presented with 1 month of severe nonbloody watery diarrhea unresponsive to intravenous fluid replacement and high-dose loperamide. Given her low serum ionized calcium (Table 1), an intravenous calcium acetate (1 mEq · kg−1 · day−1, via total parenteral nutrition) replacement therapy was initiated. Two days after calcium was replaced and her hypocalcemia improved, her diarrhea stopped (Fig. 2).
EF is a 10-year-old white boy who presented with protracted diarrhea for 3 months because of norovirus and Cryptosporidium infections. His medical history was significant for Down syndrome and posterior urethral valves leading to obstructive uropathy and end-stage renal disease, for which he underwent renal transplantation in 2004. Since then, he had been on maintenance mycophenolate mofetil, tacrolimus, and low-dose prednisone. Findings on initial physical examination revealed an obese but short child with tachycardia, dehydration, and a benign abdomen. The diarrhea was watery and nonfoul smelling. Initially, the diarrhea was mild and intermittent. Within 2 months, it progressed to become daily and copious. His laboratory values are shown in Table 1.
He was treated initially with oral nitazoxanide (200 mg twice daily for 7 days) and intravenous fluid rehydration. Diarrhea and metabolic acidosis worsened (Fig. 3). A decision was made to withhold all enteral intake, intravenous fluid administration was readjusted, and a sodium bicarbonate drip initiated; however, his diarrhea persisted (Fig. 3A). There were no abnormalities noted on esophagogastroduodenoscopy and colonoscopy.
Given his diarrhea worsened with nil per os, a diagnosis of secretory diarrhea was made, oral feeds resumed, and a trial of oral calcium carbonate (650 mg 3 times daily, 1 mEq · kg−1 · day−1) started. The child's daily stool output before and after calcium administration is shown in Fig. 3A. Following calcium administration, diarrhea dropped significantly at day 1 and normalized at day 3 (Fig. 3A). Ten days later, the patient was discharged and calcium carbonate discontinued. Twelve days after discontinuation of calcium carbonate, diarrhea recurred (Fig. 3A). Calcium therapy was restarted. One day after reinitiation of calcium therapy, diarrhea stopped. Two days later, constipation developed. As a result, calcium carbonate was discontinued and constipation subsequently resolved. One week after discontinuation of calcium carbonate, diarrhea recurred again for the third time, although it was less severe than the previous 2 episodes. Subsequent review of histology revealed positive Cryptosporidium. Stool studies were positive for Cryptosporidium. A second course of nitazoxanide was given. To avoid constipation, calcium carbonate was not given this time; instead, he was given calcium-enriched dairy products. Two weeks later, his diarrhea resolved (data not shown). During the entire period of calcium treatment, the serum calcium levels were monitored and were within the normal range (ionized Ca2+ 4.55–5.25 mg/dL) without evidence of hypercalcemia (Fig. 3B).
This case series demonstrated that calcium administration may be effective in “halting” viral and parasitic diarrhea in immunocompromised children. Complementing our observations, Bovee-Oudenhoven et al (10) have shown that calcium supplementation can reduce the severity and duration of bacterial diarrhea caused by Escherichia coli in human adult volunteers. Thus, calcium may be a general antidiarrheal agent. Indeed, people on high-calcium diets are often constipated as are patients with hypercalcemia.
It is noteworthy that the calcium therapy can be reused and its antidiarrheal effect can be reproduced in the same patient multiple times without reduction of efficacy or development of resistance; it may even enhance the sensitivity to the therapy (patient 3; Fig. 3). Although this seems unusual, it does go along with the known property of the CaSR, the primary sensing mechanism of extracellular calcium (11). Unlike most of the G protein–coupled cell surface receptors in which prior drug exposure induces “desensitization,” the CaSR is equipped with an unusual intracellular mechanism that enables “refuse” agonist-induced receptor internalization (12). Nonetheless, it is important to note that the more rapid response to the second treatment seen in patient 3 may also be simply related to diarrhea being less severe than it was at the time of the first treatment.
Figure 1 suggests a strong correlation between serum ionized calcium and stool output in patient 1; however, in patient 3, stool output was unrelated to serum calcium, and diarrhea was seen at serum calcium levels that were associated with little or no diarrhea in the first patient (Fig. 1C). The reason for the discrepancy is unknown, but it may be related to the differences between the 2 patients. For example, the level of serum calcium before therapy and the route of calcium supplementation were different between the 2 patients. Whereas patient 1 had hypocalcemia, patient 3 did not; the latter's serum calcium levels before calcium supplementation were within normal ranges. Similarly, whereas patient 1 received intravenous calcium supplementation, patient 3 did not; the latter received only oral calcium supplementation. Had luminal calcium levels been measured in patient 3, a correlation between luminal calcium and stool output also may exist.
Both direct and indirect mechanisms have been proposed to explain the calcium antidiarrheal effect. First, calcium acts via specific interaction with the cell surface–sensing receptor CaSR in the gut (6–9). Second, calcium functions via nonspecific binding to pathogens, bile acids, or fatty acids (10). Because calcium can achieve similar antidiarrheal effect via a nonmucosal route (patient 1 and patient 2), the nonspecific mechanisms seem less explanatory in the present study.
In summary, our small case series suggests that the simple nutrient calcium may be useful in rapidly “halting” infectious diarrhea. Given its rapid action, its simplicity, and its wide availability, this simple nutrient-based antidiarrheal therapy would be particularly attractive as a treatment for diarrhea in infants and young children in the developing nations, both immunocompromised and noncompromised. Clearly, large-scale trials are needed to verify its efficacy and safety.
The authors thank Dr Donald A. Novak for critical review of this manuscript.
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