Giardia lamblia (also called Giardia intestinalis or duodenalis) is a flagellate protozoa that generally causes a self-limited, often persistent illness that is typified by diarrhea, flatulence, greasy/ floating stools, bloating, abdominal cramps, dehydration, weight loss, and malabsorption [1]. It is the leading cause of human intestinal parasitic infection in the USA [2]. Although less frequently detected than giardiasis, cryptosporidiosis is a similar persistent diarrheal illness caused by protozoa of the genus Cryptosporidium [3]. Cryptosporidiosis is characterized by diarrhea (with or without crampy abdominal pain), which may be intermittent or continuous, and voluminous, and may include vomiting and low-grade fever [4,5]. Giardiasis and cryptosporidiosis are considered ‘neglected diseases’ by the World Health Organization [6]. Giardiasis is commonly treated with metronidazole or tinidazole; however, the tablet formulations can be difficult to administer in children because of pediatric dose requirements, possess an unpalatable metallic taste, and may cause adverse effects such as nausea [7,8]. In addition, resistance has been documented in G. lamblia [9-11]. Apart from nitazoxanide, there is no other commonly recommended specific treatment for cryptosporidiosis. Nitazoxanide has proven to be clinically effective in a short course (3 consecutive days) of therapy in both children (>1 year old) and adults who are otherwise healthy and is the only agent approved by the Food and Drug Administration (FDA) for the treatment of both giardiasis and cryptosporidiosis. Furthermore, with its availability as a pleasanttasting, oral suspension, it is the only FDA-approved agent available to treat persistent diarrhea caused by these parasites in young children.

Pediatric infections with intestinal parasites such as G. lamblia and Cryptosporidium spp. in the US appear more frequent than commonly perceived and have been understudied [12]. It is therefore believed that general awareness of these persistent parasitic infections may be low. A recent Centers for Disease Control and Prevention survey of obstetrician-gynecologists on their clinical and epidemiologic knowledge of cryptosporidiosis in pregnancy found that only 44% of respondents reported that prolonged, intermittent diarrhea would lead them to consider cryptosporidiosis in a differential diagnosis [13]. In addition, questions about the availability of an FDA-approved treatment were the most frequently missed questions among the survey respondents. We are not aware of any similar survey data that assesses the general awareness of Giardia and/or Cryptosporidium in any other physician group, in particular pediatricians. We therefore conducted a survey of US pediatricians to evaluate their knowledge and perceptions on the treatment of these parasitic infections in children 1-12 years of age.

Survey design and conduct

The primary objective of this survey was to gain a greater understanding of the knowledge, attitudes, and practices in the diagnosis and treatment of parasitic diarrhea among pediatricians in addition to assessing their familiarity of and receptivity to current approved drug therapy. The final goal was to ensure that the results of this survey were made available to the medical community in an effort to highlight potential gaps in knowledge and awareness of causes and treatment of parasitic infection in children and to facilitate education to close this gap.

Nielsen Co. (New York, NY) was responsible for the execution and completion of the participant surveys, submission of the survey to potential participants, collecting survey data, tabulating results, and reporting final results to the sponsor (Lupin Pharmaceuticals Inc., Baltimore, MD). The online survey was conducted from July 1 to July 14, 2014, among 1000 pediatricians and pediatric sub-specialists regarding their awareness of the causes of diarrheal illnesses and available treatment options for children. Potential survey participants were identified from Nielsen’s general pediatrician database (N = ~12,000) and 3286 were invited to participate via direct e-mail to achieve the target of 1000 respondents. Soft quotas included pediatric infectious disease specialists (n = 30) and pediatric gastroenterologists (n = 30), and the majority as general pediatricians (n = 940) (to a maximum of 1000 if soft quotas were not filled). Respondents were only included based on screening questions and had to be practicing in one of the target specialties (pediatrics, pediatrician gastroenterology, or pediatric infectious diseases), see ≥1 pediatric patient per week with diarrhea, and had been practicing clinical medicine for 2-30 years. Those who completed the survey were offered a modest honorarium ($25) for their time.

The survey was designed by Atom Strategic Consulting, LLC (Randolph, NJ) and Nielsen in collaboration with academic physicians with different specialty focus including pediatric infectious disease, pediatric gastroenterology, and epidemiology (The Persistent Diarrhea Working Group). Input on survey creation was also provided by staff from the Centers for Disease Control and Prevention (see Acknowledgments). Survey questions were organized such that general questions about diarrhea cause and treatment approach were asked first followed by specific questions about parasite awareness. This was followed by questions specific to familiarity with barriers to using nitazoxanide and then general parasite knowledge and treatmentrelated guideline questions. The survey concluded with a demographic assessment. There were a maximum of 44 survey questions that included four screening questions, five demographic questions, and 35 questions concerning diarrhea (on causes, definition, treatment, and parasite awareness) of which five had follow-up questions that would only require completion based on the response of the originating question. Survey questions and potential responses are detailed as Supplemental Data (see online).

Data analysis

Data were described descriptively as n (%) or mean ± SD for the total cohort of 1000 respondents and for pre-selected respondent subgroups defined by their particular response to survey questions (practice type, practice setting, duration in practice, cases of diarrhea seen weekly, persistent diarrhea changes suspicion of cause, caring for patients with recurrent/prolonged diarrhea, and familiarity with nitazoxanide). Statistical testing (IBM SPSS software) across subgroups was performed using the t-test with P < 0.05 considered as statistically significant.

Respondent demographics

Table 1 shows the demographic breakdown of the survey respondents. Most were general pediatricians (95.8%), which is in line with the initially targeted population for the survey. A small percentage of respondents defined their specialty as pediatric gastroenterologists (2.7%), pediatric infectious disease specialists (1.4%), and pediatric surgeon (0.1%). Gender distribution was approximately equal. Their mean duration in practice was 16.7 ± 8.14 years (Table 1).

Table 1: Pediatrician Demographics.

Survey analyses

Unless otherwise specified, the denominator for percentage calculations is based on the total of 1000 respondents.

Results are summarized in Table 2. The majority of respondents (95.0%) identified viruses as the most likely cause of diarrhea; the next most likely cause was food intolerance (3.4%) and none selected parasites. The most likely approach to treatment was reported as empirical treatment with supportive therapy alone (82.0%). The majority of respondents defined ‘persistent’ diarrhea as lasting either >1 (39.6%) or >2 (41.2%) weeks. According to the respondent’s definition of persistent diarrhea, 94.0% stated that their suspicion of the cause of diarrhea would change; among the respondents who replied yes (n = 940), the most frequent suspected causes were bacteria (39.5%), food intolerance (27.6%), and parasites (11.3%). Further, respondents who currently prescribe nitazoxanide (n = 21) were significantly (P<0.05) more likely to suspect parasites compared to those who had never heard of nitazoxanide (n = 33) [20.6% vs. 10.1%] or those who had heard of nitazoxanide but never prescribed it (n = 34) [20.6% vs. 9.5%]. The majority of respondents (82.7%) considered that there was a difference clinically between diarrhea that is ongoing compared to diarrhea that gets better but then recurs. Among those who considered there was a difference between ongoing and recurrent diarrhea (n = 827), the majority (89.8%) stated that their treatment approach would be different. Those who had been in practice for 21-30 years (n = 246) were significantly (P < 0.05) less likely to change their treatment approach compared to those who had been in practice for 2-10 years (n = 210) [85.7% vs. 92.5%] or 11-20 years (n = 287) [85.7% vs. 91.7%]. The majority of respondents stated they cared for patients with recurrent or persistent diarrhea 3-10 (17.6%), 1-2 (51.3%), or <1 times a month (28.3%). Respondents who prescribed nitazoxanide currently or in the past (n = 268) were significantly (P < 0.05) more likely to see a higher number of patients with persistent or prolonged diarrhea each month compared to those who were unfamiliar with nitazoxanide (n = 732): 32.1% vs. 15.6%, respectively, saw ≥3 patients a month (Table 2).

Table 2: Causes and Definition of Pediatric Diarrhea.

Results are summarized in Table 3. The majority of respondents would consider a parasite-induced infection after either 1 (43.3%) or 2 (44.9%) weeks with diarrhea. History and physical examination (83.9%), and duration of diarrhea (74.2%) were the primary factors for respondents to consider parasitic-induced infection. If they considered parasites as the cause of diarrhea, they would most commonly test for both Cryptosporidium spp. and Giardia spp. and initiate therapy after confirmation (70.9%). Most commonly, they would consider testing for parasites when diarrhea is considered persistent according to their definition (83.0%). Almost without exception, all had tested a child with diarrhea for parasites (98.7%). Routine fecal ova and parasite testing was most commonly used for diagnosing patients with cryptosporidiosis (89.2%) or giardiasis (82.3%). Approximately, half of respondents (54.3%) considered that a negative test for Cryptosporidium spp. was not 100% accurate (Table 3).

Table 3: Consideration of Parasitic Infection.

Results are summarized in Table 4 and Figure 1. Almost all survey respondents (97.4%) had currently or previously prescribed metronidazole to treat pediatric parasite-induced diarrhea, with considerably lower percentages of respondents being familiar with nitazoxanide (26.8%), tinidazole (16.3%), or paromomycin (13.5%) (Figure 1). The drug of first choice when considering empiric therapy was most commonly metronidazole (78.4%) with other agents being infrequently considered (paromomycin (10.4%), nitazoxanide (6.4%), and tinidazole (1.6%)). Only 18.4% of respondents knew that nitazoxanide was approved for the treatment of cryptosporidiosis and/ or giardiasis in patients ≥1 years of age. The main barrier to treating patients with nitazoxanide was a lack of awareness of nitazoxanide (59.6%). A majority of respondents (72.0%) considered that the availability of a liquid formulation of nitazoxanide would change their potential treatment choice for pediatric diarrhea (Table 4).

Table 4: Diarrhea Treatment.

Figure 1: Familiarity of respondents (N=1000) with various prescription drugs to treat.

Results are summarized in Table 5. Only 43.0% of respondents correctly identified Centers of Disease Control and Prevention/ American Academy of Pediatrics recommendation that pediatric patients with cryptosporidiosis should abstain from swimming until 2 weeks after their diarrhea had completely resolved. One-third (33.3%) of respondents correctly identified that alcohol-based hand gels and sanitizers did not inactive either Giardia spp. or Cryptosporidium spp., with the majority not knowing (38.0%) or being incorrect (38.7%). The predominant reason given by the respondents for concern over parasite transmission was transmission between the patient and caregiver/other family member (89.3%), with 36.5% citing pet-topatient transmission. Approximately half of respondents thought that burden of caring factored into their decision to treat persistent pediatric diarrhea (54.7%) and that children affected by persistent diarrhea would be fairly/very/extremely distressed by their condition (45.7%). Approximately half of respondents (56.2%) considered that print material would be the most appropriate medium for additional educational opportunity concerning parasitic infections followed by live events including web-based education (35.6%) - only 19.8% did not require additional education on this topic (Table 5).

Table 5: Parasite Awareness.

Until the present survey, there has been little published information on the knowledge, attitudes, and approach to diagnosis and treatment of parasitic diarrhea among pediatricians in general practice. The number of survey respondents (N=1000) was sufficiently large to provide a representative sample of the target pediatrician population. Respondents had to have treated at ≥1 child ages 1-12 years every week and be in practice for 2-30 years. A potential limitation was responder bias in that only about one-third of pediatricians responded to the e-mail survey.

Almost all pediatricians (95.0%) think of viruses as the most likely cause of diarrhea in young patients on initial presentation and therefore treat empirically with supportive therapy (82.4%). However, if diarrhea is persistent, they are more likely to suspect bacteria (39.5%) or food intolerance (27.6%), with one in ten suspecting parasites (11.3%). They were split evenly in their definition of diarrhea persistence between >1 and >2 weeks (41.2% and 39.6%, respectively). Approximately threequarters of pediatricians (71.3%) reported caring for ≥1 patient per month with recurrent and/or persistent diarrhea, with about one in five (20.0%) reporting ≥3 patients monthly. Almost all pediatricians would consider a parasite-induced infection after about >1 or >2 weeks (44.9% and 43.3%, respectively), while ~5% cited that they do not usually think about parasitic infection. History and physical exam (83.9%) and duration of diarrhea (74.4%) were the primary considerations for parasitic-induced infection, with about one-third (36.2%) only considering parasites when all other possible causes had been ruled out. Delayed recognition and treatment (83.3%), prolonged morbidity (73.5%), lost productivity and general inconvenience to caregivers (70.2%), and transmission to others (65.5%) were concerns for most pediatricians. Giardia (80.9%) was the most frequent parasite seen in their pediatric practice followed by Cryptosporidium (27.7%) and other parasites (12.0%), with about one in ten (9.8%) not seeing parasites. If considering parasites as the cause of diarrhea, most test for Giardia and Cryptosporidium (70.9%) or Giardia alone (12.1%) and initiate drug therapy after confirmation. Routine fecal ova and parasite testing for Giardia (82.3%) and Cryptosporidium (89.2%) was the most common test used for diagnosis.

Given these findings with respect to the causes and definition of pediatric diarrhea and consideration of parasitic infection in children, it is important to bear in mind recent reports of the potential for long-term complications from parasitic infections [14,15]. Six years after a waterborne Giardia outbreak, [15] the prevalence of irritable bowel syndrome (39.4%) and chronic fatigue (30.8%) were elevated and significantly increased (relative risk approximately 3-fold higher) compared to matched controls. Compared to results 3 years previously, [14] the prevalence of both conditions decreased over time. Thus, Giardia infection may elicit very long-term, but slowly self-limiting, complications. Prompt, appropriate treatment of parasite-induced diarrhea is therefore important to minimize the potential for any long-term morbidity and may be an underestimated concern for some pediatricians.

Metronidazole was the first choice among survey responders for empiric drug therapy for parasite-induced infections (78.4%) followed by paromomycin (10.4%) and nitazoxanide (6.4%). This was despite the general recognition that metronidazole is difficult to administer in children: it generally needs to be administered as 3-times daily for 10 days and has a bitter metallic taste, particularly when tablets have to be divided as no standard oral pediatric liquid formulation is available [7,8]. Metronidazole also induces adverse effects and resistance occurs in G. lamblia [8-11]. Notably, about three-quarters (72.0%) of pediatricians considered that the availability of a liquid formulation of nitazoxanide would change their potential treatment choice for diarrhea. Nitazoxanide is available as a pleasant-tasting pediatric oral suspension for administration using a twice-daily regimen for 3 days. There was poor awareness of the age range for which nitazoxanide is approved by the FDA as approximately two-thirds (63.2%) of respondents did not know; in actuality, the pediatric formulation is approved for children ages 1-11 years and as tablets for those ages >12 years. Furthermore, nitazoxanide is the only medication that is FDA approved for the treatment of both Giardia and Cryptosporidium infection.

Just less than half of pediatricians (43.0%) correctly recognized Centers for Disease Control and Prevention/American Academy of Pediatrics recommendations that patients diagnosed with cryptosporidiosis should abstain from swimming until at least 2 weeks after their diarrhea has completely resolved. Transmission of Cryptosporidium and Giardia via recreational water activity (e.g. swimming in public pools, recreational parks, rivers, lakes, rivers) appears relatively frequently and is associated with seasonal peaks in infections during the summer [16-18]. One-third (33.3%) of pediatricians correctly identified that alcohol-based hand gels and sanitizers do not effectively inactivate either Giardia or Cryptosporidium, while 38.0% did not know. To receive additional education concerning parasitic infections, respondents preferred additional print materials (56.2%) followed by live events including web-based education (35.6%).

In conclusion, the results of this survey supports the need to enhance efforts to provide education among general pediatricians on how best to manage and effectively treat childhood diarrhea caused by parasites such as Giardia and Cryptosporidium.

We would like to thank Jonathan S. Yoder, MSW, MPH, and Michele Hlavsa, RN, MPH, (Centers for Disease Control and prevention, Atlanta, GA) for their input into the creation of the survey. Medical writing assistance provided by Peter Todd, PhD, of Tajut Ltd. (Kaiapoi, New Zealand) was supported financially by Lupin Pharmaceuticals, Inc. during the preparation of this manuscript.