Rotavirus infections cause severe disease, leading to approximately 611,000 deaths per year in children worldwide.1 However, global rotavirus mortality is not evenly spread, with most of the fatalities occurring in developing countries.2 The fact that outcomes are more often severe in developing countries is attributed to inadequacies in healthcare services resulting in poorer access to basic rehydration therapies and to a higher prevalence of malnutrition.2 In more general terms, the poorer health status of children may be a contributing factor, including the possibility of coinfections with other microbial agents, such as enteric pathogens. These major health problems in the developing world impact negatively on morbidity and mortality, as well as on cognitive and physical development.3
Coinfections with rotavirus can also be problematical in industrialized countries, particularly those with temperate climates. In these areas, rotavirus infections cause the highest number of disease cases during the winter and spring months.4,5 This coincides with the peak incidence of acute viral respiratory tract infections, such as with influenza viruses and respiratory syncytial virus (RSV).6,7 Such overlap in seasonality places a considerable strain on healthcare systems and increases the potential for nosocomial rotavirus infections. Rotavirus is the leading cause of pediatric nosocomial diarrhea in Europe7 and can be a major problem for neonates in intensive care units.8
Two new oral live-attenuated rotavirus vaccines (Rotarix, GlaxoSmithKline, Rixensart, Belgium; and RotaTeq, Sanofi Pasteur-MSD, Lyon, France) have recently become available and offer a new chance for better control of rotavirus disease. It is expected that introducing rotavirus vaccination into childhood immunization programs will substantially reduce the associated mortality in developing countries and virtually eliminate rotavirus hospitalizations in industrialized nations.9
This review will address the issue of rotavirus coinfections. Firstly, it will be established to what extent rotavirus coinfections with other pathogens actually occur, including the types of pathogens involved, focusing on clinical observations. Secondly, the impact of coinfections will be examined, ie, whether the outcome of rotavirus infection is influenced by coinfection with another pathogen (viral, bacterial, or parasitic) and which types of interactions may occur. Given the lack of data in humans, this necessitates expansion of the discussion to include published in vitro laboratory research and animal model data, as well as clinical observations. Finally, rotavirus coinfections with other organisms will be discussed in the context of rotavirus vaccination. It will be considered whether rotavirus vaccination may: (1) influence the severity or outcome of other gastrointestinal diseases in children in the developing world and (2) mitigate the problems associated with winter seasonality and nosocomial infections in industrialized nations.
MATERIALS AND METHODS
An extensive PubMed search was performed in January 2007, involving papers/abstracts in English. From the initial search, for ‘rotavirus’ plus either ‘co-infection’ (or ‘coinfection'), ‘mixed’ or ‘interaction’, a list of 506 references was generated. The references were then reviewed individually to identify those of potential relevance (ie, relating to rotavirus infection and coinfection with other microorganisms; n = 127). Furthermore, separate searches were carried out for ‘rotavirus’ plus other specific microorganisms identified during the first stage. Of the 2073 references identified in this way, and after individual review of abstracts, 45 additional papers were identified as potentially relevant, and then reviewed in full. Any additional sources were identified from the bibliographies of these references or from the authors’ own libraries and expertise.
Rotavirus Infection and Coinfections
Table 1 shows the results of clinical observations investigating the types of organisms that have been observed in rotavirus coinfections and identifies viruses, bacteria, and protozoa as coinfecting microorganisms.10–25 Those were: astrovirus (2.0–19.2%),10,12,15,20,22,23 norovirus (2.4–23.5%),16,17,19,22,23 adenovirus (1.0–8.8%),16,17,20,23,25 picornavirus (1.2%),16 sapovirus (1.5%),19 any Campylobacter (1.0–3.2%),11,20 any Salmonella (0.5–4.8%),11,20 any Escherichia coli (11.1–45.5%),11,14,21,24 any Giardia (1.7–8.6%),13,24 and Shigella flexneri (3.2–8.0%).11,18 Occasionally, rotavirus was found to coinfect with more than 1 microorganism (Table 1).
The following describes the clinical outcomes of coinfections with rotavirus and other pathogens, starting from a review of in vitro experiments and animal model studies.
In Vitro Data
Several in vitro studies have looked at pre- or coinfection of cultured cell lines with rotavirus and other pathogens. MA104 cells (derived from embryonic monkey kidney) were infected with rotavirus and enterobacteria (Salmonella typhimurium, S. flexneri or enteroinvasive E. coli), either concurrently or after preinfection with rotavirus.26 Preinfection with rotavirus enhanced the invasiveness of S. typhimurium, S. flexneri and enteroinvasive E. coli. However, 2 control strains of nonenteropathogenic E. coli did not become invasive in cells preinfected with rotavirus.
When Caco-2 cells, derived from a human colon tumor and remaining polarized in vitro, were preinfected with rotavirus they were more susceptible to infection with enteroinvasive Yersinia spp. than non-preinfected controls. The authors concluded that rotavirus infection enhances early Yersinia-host cell interactions required to initiate Yersinia infection.27
Caco-2 cells were preinfected with rotavirus or poliovirus and superinfected with Listeria monocytogenes.28 Increased L. monocytogenes internalization occurred in cells preinfected with rotavirus, whereas preinfection with poliovirus had a slight interfering effect on bacterial growth. Enhanced bacterial replication occurred in cells coinfected with rotavirus and L. monocytogenes compared with controls infected with L. monocytogenes alone. In contrast, poliovirus and L. monocytogenes-coinfected cultures had lower bacterial replication levels than controls infected with L. monocytogenes alone.
Thus, although a range of in vitro experiments have demonstrated that coinfection of cells with rotavirus and a variety of bacterial pathogens can increase bacterial replication and/or invasiveness, not all in vitro systems have shown that preinfection of mammalian cell lines with rotavirus increases the susceptibility of host cells to bacterial pathogens. For example, preinfection of Caco-2 cells with rotavirus did not affect adhesion or internalization of 3 strains of Campylobacter jejuni.29
Studies in Animal Models
Experimental animal model studies with calves, piglets, lambs, mice, and rabbits have shown the impact, or potential impact, on outcome after infection with rotavirus and other gut pathogens. Infection of calves with rotavirus followed by infection with enterotoxigenic E. coli (ETEC) within 2–4 days induced diarrhea independently of age, but mono-infections with rotavirus or ETEC only resulted in diarrhea when calves were less than 7 days or 24 hours old, respectively.30 This study showed that ETEC-induced diarrhea was age-related, and that the lack of diarrhea in older calves infected with ETEC could be reversed by mixed infections with rotavirus.
These data were complemented by another study conducted with 6-day-old calves infected with either rotavirus, ETEC, or both.31 Infection with rotavirus alone consistently resulted in diarrhea, whereas ETEC inoculation did not lead to diarrhea, and ETEC intestinal colonization did not occur. In dual infections, both rotavirus and ETEC multiplied, but diarrhea severity was not greater than after rotavirus mono-infection. The results suggested that prior or simultaneous rotavirus infection is required to allow ETEC intestine colonization in calves of this age.
Rotavirus and enteropathogenic E. coli (EPEC) may also have an impact on each other in calves, leading to worse clinical outcomes such as dehydration and death.32 This was shown by a study in which a single, small dose of EPEC resulted in mild diarrhea, and mono-infection with rotavirus also caused diarrhea but not dehydration or death. However, in combination, nonlethal doses of the 2 pathogens caused severe dehydration and death. A scanning electron microscopy study of gut tissues of calves infected with rotavirus and/or EPEC revealed that infection with rotavirus alone resulted in the abomasum (ie, the fourth stomach compartment) being covered with an abundant mucous film.33 However, coinoculation with rotavirus and EPEC not only resulted in severe diarrhea, but also severe erosion of the whole digestive tract, even the abomasum and colon.
In 107 samples from neonatal calves with diarrhea (n = 134), rotavirus and/or coronavirus were identified.34 In 58 cases (54%), both rotavirus and coronavirus were present, whereas rotavirus and coronavirus were found singly in 15 (14%) and 34 (32%) of cases, respectively. As 107 of 134 (80%) diarrheal samples contained rotavirus and/or coronavirus, both of these viruses were considered to be associated with diarrhea in young calves. Moreover, other viruses (togavirus, enterovirus, herpesvirus) found in 7% of cases always occurred in association with rotavirus and/or coronavirus. In a separate study, when fecal samples from 218 calves (aged 1–30 days) were screened for the presence of rotavirus, 93 samples were positive of which 39 (41.9%) contained rotavirus as the only enteropathogen.35 However, other enteropathogens, even multiple organisms, were found in conjunction with rotavirus [ie, Cryptosporidium (85.2%), coronavirus (20.4%), and E. coli (16.7%)]. Another study of calves, under 30 days of age with diarrhea (n = 218), showed that rotavirus and coronavirus are commonly detected in the same fecal sample (in 87% of cases).36 Furthermore, when calves aged 22 days or younger were infected with astrovirus alone, or mixed with rotavirus, those infected with astrovirus alone did not have diarrhea, whereas a mixed infection resulted in severe diarrhea (however, calves infected with rotavirus alone were not included in this study).37
Three-day-old piglets (n = 59) were orally inoculated with either rotavirus, ETEC, or both pathogens (rotavirus was given at 3 days of age, followed by ETEC 24 hours later).38 Piglets infected with both (rotavirus and ETEC) developed more severe diarrhea compared with those given either agent alone at the same dose, and all dually inoculated piglets died between 3 and 6 days after inoculation (no piglet given either pathogen in isolation died). Similar results were found for 4-week-old piglets given either rotavirus, EPEC, or both agents sequentially.39 Although EPEC alone produced more serious diarrheal disease than rotavirus alone, when both pathogens were given sequentially the resulting diarrhea was more severe than after either agent given alone. In contrast to these results, experiments in which 1-day-old piglets (n = 54) were infected orally with either rotavirus, enterovirus, or both concurrently, showed that a mixed inoculum partially mitigated the clinical effects observed with rotavirus infection alone.40 Enterovirus alone did not induce diarrhea or intestinal lesions, even though infection was established in all inoculated piglets. Rotavirus alone produced severe diarrhea through widespread villous destruction. Inoculation with rotavirus plus enterovirus resulted in some reduction in villous damage compared with rotaviral mono-infection, and was accompanied by a moderation in clinical signs and premature mortality. By 48 hours after inoculation, 12 out of 19 piglets given rotavirus alone were moribund and 3 had died, whereas none of the dual-infected piglets had become moribund or had died. These results suggested a partial inhibition of rotavirus replication by enterovirus infection.
In experiments with lambs infected with EPEC or rotavirus, either pathogen given alone induced diarrhea.41 However, when lambs were inoculated with a mixture of EPEC and rotavirus the mortality rate was higher than for either agent given alone, though the duration of diarrhea was not longer. Experiments with 4-day-old mice have also shown potentiation between rotavirus and E. coli infections leading to increased premature mortality.42 When rabbits aged 10–16 weeks were inoculated with rotavirus and/or E. coli 015:H-(RDEC-1), mono-infection with E. coli produced mild diarrhea, but in combination with rotavirus premature mortality and morbidity increased because of diarrheal disease.43
In conclusion, combined infections of different animals with rotavirus and several bacterial enteropathogens led to an increased severity of disease. The molecular mechanisms underlying these observations remain to be elucidated.
The impact of rotavirus infection on infections with other viral enteropathogens has been noted in several clinical observations. A 14-month-old infant suffered from 2 attacks of rotavirus gastroenteritis, with the second episode occurring within 1 month of the first, and preceded by a mild case of adenovirus-associated gastroenteritis.44 The second episode of rotavirus gastroenteritis resulted in more severe gastrointestinal symptoms than the first, with both rotaviral infections associated with more severe symptoms than the adenovirus infection. An initial natural rotavirus infection would normally be expected to provide a degree of protection against subsequent infections, and thus reduce the severity of diarrheal symptoms.45 As the second episode of rotavirus gastroenteritis was more severe than the first, and preceded by an adenovirus infection, it is suggested that an interaction could possibly have occurred between adenovirus and rotavirus to increase the severity of the child's symptoms. However, it should be noted that at the time (1979), rotavirus serotyping was not yet available, and the second rotavirus infection could have been by a different serotype/genotype.
It seems possible that rotavirus and astrovirus infections in young children may impact on each other, leading to more severe diarrhea, particularly as most children have been infected by astrovirus (and rotavirus) by 6 years of age.46 Isolated human astrovirus infections tend to be associated with milder symptoms (less severe diarrhea for a shorter duration, lower likelihood of fever and/or shorter duration of vomiting episodes) than mono-infections with rotavirus.46 A study conducted in U.S. children (n = 214) showed that coinfection of astrovirus with another enteropathogen resulted in more frequent diarrhea than astrovirus infection alone.47 However, in this study only 11 out of 26 diarrheal episodes were because of a mixed infection, and only 1 mixed infection was caused by rotavirus plus astrovirus. In another study in Spanish children (n = 820), coinfection of rotavirus and astrovirus (n = 13) resulted in a higher mean Ruuska/Vesikari score than in children infected with astrovirus alone [n = 23, 11 (6–16) versus 8 (4–12), respectively], suggesting that coinfection of these 2 agents results in more severe gastroenteritis.20 More clinical evidence is required to demonstrate an interaction between members of these 2 viral families.
Like rotavirus disease, infection with human immunodeficiency virus (HIV) and its clinical sequelae are a particular problem in the developing world. The coexistence of HIV and rotavirus infections together with malnutrition in developing countries could potentially lead to increased disease severity. A study conducted in Zambia showed that rotavirus and HIV concurrently infected 132 (24.6%) of 537 infants under 5 years of age hospitalized with diarrhea.48 Dehydration was most common in infants coinfected with rotavirus and HIV, but mortality rates were similar for HIV-positive patients, regardless of coinfection with rotavirus.48 Malawian children under 5 years of age and attending hospital for acute gastroenteritis as inpatients (n = 786) or outpatients (n = 400) were enrolled in a study to examine the effect of HIV infection on rotavirus gastroenteritis.49 Children with rotavirus diarrhea, with or without HIV, were followed up for up to 4 weeks after hospital discharge. Rotavirus was detected less frequently among HIV-infected children [102 of 336 (30%)] than HIV-uninfected children [348 of 850 (41%)] (relative risk 0.71; 95% CI: 0.53–0.87; P = 0.0007). This may be related to the gastrointestinal effects of other enteropathogens in children with HIV infection (ie, patients were diagnosed with these infections, in the presence of rotavirus). There were no differences in the severity of rotavirus disease in hospitalized children with and without HIV infection, but HIV-infected children were more likely to die during follow up [11 of 50 (22%)] than HIV-uninfected children [0 of 61 (0%); P < 0.0001]. However, this increased mortality was more due to the sequelae of HIV infection and disease. When stool specimens from 198 consecutive adult hospital admissions to a general ward were tested, the prevalence of enteric viruses did not differ significantly between patients with or without HIV infection.50 A Venezuelan study in which 125 stools were collected from patients with HIV, with or without diarrhea, showed that enteric viruses were detected in only 8 (6.4%) samples.51 Another study conducted in Venezuelan children, positive (n = 27) or negative (n = 38) for HIV infection, found similar rates of virus-associated diarrhea for these 2 groups.52 In summary, the studies cited above do not support a major role for enteric viruses, including rotavirus, in diarrheic episodes experienced by patients with HIV.50–52
In a study in Brazil, children aged 5 years or younger and suffering from acute diarrhea (n = 154) were evaluated for fecal pathogens.24 Bacteria were the most frequently found group of pathogens [53 of 154 cases (34.4%)], followed by rotavirus [32 of 154 (20.8%)] and 2 (1.4%) cases of G. lamblia; 25 of 154 (16.2%) cases were mixed rotavirus/bacterial infections. Of the 105 bacteria isolated, 90 were E. coli (EPEC, 27; diffusely adherent E. coli, 24; ETEC, 21; enteroaggregative E. coli, 18). Children with a mixed (rotavirus and bacterial) infection had the highest incidence of severe vomiting and dehydration among this cohort of 154 children (Table 2).
In another study, involving 225 Ghanaian children of preschool age with acute gastroenteritis, 157 (69.8%) had mild dehydration and 68 (30.2%) had severe dehydration.53 Children who had mixed rotavirus/bacterial infections were more likely to have severe than mild dehydration. In a study carried out in Iran on 197 children under the age of 3 years with diarrhea and ETEC infection, the mean number of stool productions per day was much higher and duration of diarrhea was longer in patients with ETEC and rotavirus than those with only an ETEC infection (P < 0.001 for both parameters).14 A study of children aged 3 weeks to 13 years admitted to hospital with acute gastroenteritis compared the clinical and laboratory features of rotavirus diarrhea (n = 168) with those of diarrhea caused by enteric adenoviruses (n = 32), bacterial infections (n = 42), mixed bacterial and viral infections [n = 16; most commonly rotavirus and E. coli (n=13)], and nonspecific infections (n = 135).54 Mixed infections caused longer-lasting diarrhea (mean 8.0 days) than rotavirus infections alone (mean 5.9 days), but with a similar level of illness severity. By contrast, another study has shown that the severity of mixed infections of rotavirus and E. coli was similar to that with rotavirus mono-infections.55
Protozoan Parasitic Infections.
There are a lack of data concerning potential interactions between rotavirus and protozoan parasitic infections, but several studies have investigated G. lamblia in this respect. Bedouin infants (n = 238) were followed-up from birth to 18–23 months.56 This study showed that diarrheal episodes were more severe in children infected with rotavirus alone (n = 12) than in cases where there was a mixed infection with rotavirus plus G. lamblia (n = 3), according to age-adjusted mean scores of illness severity (80.9 versus 58.8, respectively; P = 0.03). However, the number of relevant cases was small.
‘Rotavirus syndrome’ has been described in the literature where it is proposed that rotavirus infection, possibly in conjunction with other pathogens, leads to respiratory symptoms.57–59 A hospital study identified rotavirus in 51% of 152 children with diarrhea, and a respiratory illness was described in 66% of rotavirus patients, usually preceding gastrointestinal symptoms.57 Rotavirus was detected in the stools of 5 children with sudden infant death syndrome over a 3-week period.58 Although none of the children had acute gastroenteritis, 4 of 5 had acute upper respiratory tract infections. Rotavirus was also identified in tracheal aspirates from 2 of the infants. Extensive investigations failed to reveal the presence of any other viruses or toxins in specimens obtained from the 5 children with sudden infant death syndrome. The possible association between respiratory tract manifestations and rotavirus infection was investigated by testing for human rotavirus antigen and RSV antigen in tracheal aspirates of children (n = 58) with pneumonia.59 Rotavirus antigen was detected in 16 of 58 (27.6%) cases, and RSV antigen in 27 of 58 (46.5%) cases, with both detected in 4 of 58 (6.9%) children. In the authors’ opinion, these results suggest that rotavirus may occasionally be a causative agent of acute lower respiratory infections in children, and that it may be transmitted via a respiratory route. However, rotaviruses are generally not accepted as the cause of respiratory tract infections. A study of 283 children with diarrhea showed that while 34% of children infected with rotavirus exhibited diarrheal and respiratory symptoms, respiratory symptoms were also present in 25% of those uninfected with rotavirus or adenovirus.60 Thus, an association between rotavirus infection and respiratory symptoms (or the existence of a rotavirus syndrome) could not be confirmed. Furthermore, in a prospective study of children referred to hospital, rotavirus was identified in 37% of 128 patients with acute gastroenteritis.61 One or more signs of upper respiratory tract illness were observed in 36% of the patients with rotavirus gastroenteritis and in 35% of those with nonrotavirus gastroenteritis. A similar study of 197 episodes of acute gastroenteritis in 109 children during a 12-month period also failed to show that rotavirus was associated with upper respiratory tract manifestations.62 One or more upper respiratory tract manifestations were observed in 39% of children with rotavirus gastroenteritis, but also in 36% of rotavirus-negative cases of gastroenteritis. Likewise, a study conducted in South African children (n = 1672) aged 0–12 years, failed to find a rotavirus syndrome associated with respiratory symptoms and/or pyrexia in patients with a rotaviral infection as these occurred with equal frequency in patients not infected with rotavirus.63 Furthermore, in a study of 202 infants with bronchiolitis, there was no evidence that simultaneous rotavirus and respiratory infections (ie, RSV) were associated with increased severity of bronchiolitis.64 Thus, the existence of a rotavirus syndrome cannot be substantiated, and upper respiratory tract illnesses in patients with rotavirus gastroenteritis are more likely to be caused by a separate infection with another pathogen occurring coincidentally.
Potential Impact of Rotavirus Vaccination
Whether rotavirus vaccination can have a positive effect on disease outcomes in the context of coinfections has been inadequately studied. However, it is of interest to note that rotavirus vaccination may have a benefit in children infected with pathogens other than rotavirus that cause diarrhea.65,66 In a placebo-controlled trial of rotavirus vaccination in children between 50 and 110 days of age, 86 of 1528 episodes of diarrhea were positive for enteric adenovirus infection alone (12 cases of mixed rotavirus-adenovirus infections were excluded).65 Compared with a vaccine placebo, the rotavirus vaccine group had a shorter duration of watery diarrhea in these pure enteric adenovirus-associated cases (P = 0.008). Stool samples (n = 1432) were also obtained from another placebo-controlled rotavirus vaccine trial.66 In this instance, sapovirus was detected in 132 (9.2%) of the samples, and in 80 (5.6%) of stools as the sole gastroenteritis virus. Although the proportion of sapovirus-associated cases was similar in the rotavirus vaccine and placebo groups, those in the vaccine group had a shorter duration of diarrhea and a reduced frequency of diarrhea. The mechanism by which rotavirus vaccine may impact on either adenovirus or sapovirus infections is unknown.
From the literature it is clear that many rotavirus infections occur as mixed infections with other microorganisms, including viruses, bacteria, and protozoa. In the studies cited in this review, the incidence of mixed infections was 0.3–45.5%. It is likely that the wide range reflects differences in local epidemiology, economic development, and hygiene conditions.
In vitro, animal and clinical studies provide evidence for potentiation between rotavirus infection and coinfecting pathogens. In general, but not exclusively, this results in a poorer prognosis. It should be stressed that the precise mechanisms by which rotavirus influences the invasiveness, growth, or pathogenicity of another pathogen are poorly studied and not understood. Suggested mechanisms for rotavirus-associated changes to bacterial invasiveness include effects on phagocytosis or membrane receptors,28 and general effects on the cell membrane or the cytoskeleton.26 Coinfection with a viral and bacterial agent often produces more severe disease than mono-infection, possibly explained by nonspecific virus-associated effects on the host rendering it more susceptible to bacterial disease.28 Such general effects may contribute to potentiation effects between rotavirus and specific pathogens. Other mechanisms may be related to the timing of the 2 infections31 or to the more severe intestinal lesions observed after certain dual infections.41
It should be noted that most studies cited investigate the presence of organisms in stool samples and that it is often difficult to directly attribute observed symptoms to the detection of an agent. To confirm the association, it is necessary to demonstrate true replication in the course of the illness and an immunologic response towards the pathogen.
The evidence for potentiation between infections with rotavirus and bacterial enteropathogens—particularly E. coli—is strong. A number of large clinical investigations have shown that children infected with rotavirus plus a bacterial enteropathogen suffer from more severe diarrhea and/or dehydration, with diarrhea often lasting longer than in those infected with rotavirus alone.
Rotavirus gastroenteritis is now considered to be a vaccine-preventable disease.67 To achieve reduction of the morbidity and mortality associated with rotavirus, it is essential that universal mass vaccination programs are instigated. In developing countries, rotavirus vaccination could improve the poor prognosis associated with bacterial enteropathogen-rotavirus coinfections. In industrialized countries, universal childhood rotavirus vaccination could reduce the number of cases of nosocomial rotavirus infections in children already suffering severe symptoms related to other infectious agents or noninfectious diseases.
In summary, rotavirus vaccination may have a positive impact on the course of disease involving other gastrointestinal pathogens, preventing potential exacerbations and providing benefits to the individual and society as a whole. However, further studies are needed to define the exact role of rotavirus vaccination in the context of coinfections.
The authors thank Elisabetta Franco, Hans-Iko Huppertz, Zsófia Meszner, Jacek Mrukowicz, Nuran Salman, Vladimir Tatochenko, and Timo Vesikari for their input in developing this manuscript. The input of Carlo Giaquinto is particularly appreciated. Thanks are also due to Susan Brackenridge, Alison Lovibond, and Diane Sutherland for their support in preparing the manuscript.
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