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Hepatology
HCV iatrogenic and intrafamilial transmission in Greater Cairo, Egypt
  1. A Paez Jimenez1,
  2. N Sharaf Eldin2,
  3. F Rimlinger3,4,5,
  4. M El-Daly6,7,
  5. H El-Hariri2,
  6. M El-Hoseiny2,
  7. A Mohsen2,
  8. A Mostafa2,
  9. E Delarocque-Astagneau1,
  10. M Abdel-Hamid6,8,
  11. A Fontanet1,
  12. M K Mohamed2,
  13. V Thiers3,4,5
  1. 1Institut Pasteur, Emerging Diseases Epidemiology Unit, Paris, France
  2. 2Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  3. 3Virology Department, Institut Pasteur, Paris, France
  4. 4INSERM U785, Villejuif, France
  5. 5Université Paris SUD, Orsay, France
  6. 6Viral Hepatitis Research Laboratory, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
  7. 7National Liver Institute, Menoufia University, Egypt
  8. 8Department of Microbiology, Faculty of Medicine, Minia University, Egypt
  1. Correspondence to Dr Arnaud Fontanet, Unité d'Epidémiologie des Maladies Emergentes – Institut Pasteur, 25 Rue du Docteur Roux – Bâtiment Laveran 3ème étage – 75724 Paris Cedex 15, France; fontanet{at}pasteur.fr

Abstract

Objectives To document hepatitis C virus (HCV) intrafamilial transmission and assess its relative importance in comparison to other current modes of transmission in the country with the largest HCV epidemic in the world. HCV intrafamilial transmission was defined as HCV transmission among relatives living in the same household.

Design Case–control study. Cases were adult patients with acute hepatitis C diagnosed in two ‘fever hospitals’ of Cairo. Controls were adult patients with acute hepatitis A diagnosed in the same two hospitals, and family members of cases. All consenting household members of cases provided blood for HCV serological and RNA testing. Homology of viral sequences (NS5b region) within households was used to ascertain HCV intrafamilial transmission. Exposures at risk for HCV during the 1–6 months previous to onset of symptoms were assessed in all cases and controls.

Results From April 2002 to June 2007, 100 cases with acute hepatitis C, and 678 controls (416 household members and 262 patients with acute hepatitis A) were recruited in the study. Factors independently associated with HCV infection and their attributable fractions (AFs) were the following: having had a catheter (OR=5.0, 95% CI=1.4 to 17.8; AF=6.7%), an intravenous perfusion (OR=5.8, 95% CI=2.5 to 13.3; AF=20.1%), stitches (OR=2.0, 95% CI=1.3 to 6.6; AF=10.7%), gum treatment (OR=3.7, 95% CI=1.1 to 11.9; AF=3.8%) and being illiterate (OR=2.4, 95% CI=1.4 to 4.4). Of the 100 cases, 18 had viraemic HCV-infected household members. Three long-married (>15 years) couples were infected with virtually identical sequences and none of the three index patients reported any exposure at risk, suggesting HCV intra-familial transmission.

Conclusion While three new HCV infections out of 100 could be linked to intra-familial transmission, parenteral iatrogenic transmission (dental care included) was accountable for 34.6% of these new infections. Thus, the relative contribution of intrafamilial transmission to HCV spread seems to be limited.

  • Hepatitis C virus
  • risk factors
  • transmission
  • epidemiology
  • phylogeny
  • Egypt, acute hepatitis
  • epidemiology
  • HCV
  • molecular epidemiology

https://doi.org/10.1136/gut.2009.194266

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    Significance of this study

    What is already known about this subject?

    • Whether HCV transmission could be linked to living with a chronic HCV infected person has long been debated. While anti-HCV seropositivity is at least 5- to 10-fold higher in individuals living with an HCV-positive patient compared with the general population, sharing of at risk behaviours exposing to HCV or sharing of genes predisposing to HCV infection could be alternative explanations to intra-familial clustering of HCV infections.

    What are the new findings?

    • In this study based in the country with the highest HCV prevalence worldwide, HCV intra-familial transmission, defined as HCV transmission among relatives living in the same household, contributed to less than 5% of all new acute hepatitis C cases diagnosed in two ‘fever hospitals’.

    • HCV intra-familial transmission occurred among three long-married couples, in circumstances which could not be elucidated.

    How might it impact on clinical practice in the foreseeable future?

    • There is currently no basis for modifying the existing recommendations (eg, not sharing sharp items such as razors) for HCV prevention at the household level.

    • Many new cases of HCV infection were due to healthcare procedures, such as catheterisation, intravenous perfusion, stitches and gum treatment. Prevention of HCV nosocomial transmission should remain the priority.

    Introduction

    While it has been commonly observed that hepatitis C virus (HCV) infection tends to cluster within households,1 the reasons for this are not yet fully understood. HCV is primarily transmitted through direct parenteral routes (eg, blood-contaminated injections or intravenous drug use)2 3 and mother-to-child transmission rarely occurs (<5%) in the absence of co-infection with the HIV.4 Still, anti-HCV seropositivity might be 5- to 10-fold higher in individuals living with an HCV-positive patient compared with the general population.3 Possible explanations are (1) familial sharing of genes predisposing to HCV infection,5 (2) familial sharing of at risk behaviours exposing to HCV infection, and (3) intra-familial transmission, possibly sexual or domestic (ie, unapparent parenteral transmission through sharing of nail trimmers or other grooming items such as razors or toothbrushes). Intra-familial transmission by other means than blood is biologically plausible, since HCV RNA has been detected in semen,6 cervical smears7 and saliva8 9 of infected patients; nevertheless, it remains to be proved that this RNA represents infectious HCV.10

    Egypt has the highest HCV antibody prevalence in the world.11 The start of the epidemic is attributed to insufficiently sterilised intravenous injections during the mass anti-schistosomiasis treatment campaigns in rural areas during the 1970s.12 Spread of HCV has therefore been studied mainly in rural areas. An early survey documented HCV clustering among households of individuals with history of parenteral treatment for schistosomiasis.13 More recently, in cohort studies of rural areas of Egypt, having an anti-HCV-positive family member was the strongest predictor for incident HCV infection, after adjustment for iatrogenic and community exposures.14 Also, a mathematical model estimated that within HCV-infected couples, 6% would have acquired their infection from their partners.15

    Finally, in a village surveyed by our team, children with infected siblings had a 20-fold increase in risk of infection.5

    Precise data on urban areas (45% of the Egyptian population in 2000) are scarce. In 1996, HCV antibody prevalence in urban areas was estimated around 9.1% during a national survey.16 In a previous study on risk factors for acute HCV infection in Greater Cairo, intravenous injections for medical purposes, stitches and intravenous drug use were independently associated with an increased HCV risk.17 To document HCV intrafamilial transmission and to assess its relative importance in comparison to current modes of transmission, we examined sequences of acute hepatitis C cases and of their viraemic family members and conducted a case–control study on HCV risk factors in the same population.

    Patients and methods

    Participants' recruitment and ascertainment of exposure to risk factors

    A screening for acute hepatitis in the two ‘fever’ hospitals, Abbassia and Imbaba, serving all the population of Greater Cairo, allowed identification of patients recently infected with HCV. Acute hepatitis C cases were defined as inpatients and outpatients with recent (<3 weeks) fever or jaundice, positive HCV RNA with either negative anti-HCV antibody or, if with positive anti-HCV antibody, alanine aminotransferase (ALT) ≥20 times the upper limit for nitrogen (ULN) (ie, ≥400 IU/l), negative serology/PCR for other infectious agents (HAV, HBV, HEV, Epstein–Barr virus (EBV), cytomegalovirus (CMV), toxoplasmosis), no history of drugs or pesticides exposure, and no other cause of hepatitis (eg, autoimmune hepatitis, ischaemic liver injury, Wilson disease).

    The recruited hepatitis C cases were invited to ask their household members to participate in the survey. If they agreed, their household members were contacted by a trained physician and an appointment with those willing to take part in the study was set. As general rule only households where at least 75% of all members agreed to participate, except for children less than 5 years (exclusion criteria) were included. Due to the extremely low HCV prevalence among children, it is very unlikely that they contributed much to intra-familial HCV transmission. Of the 310 acute hepatitis C cases identified at the two ‘fever’ hospitals between April 2002 to June 2007, 100 (32%) were included in this study. They were older than the 210 acute HCV patients with households not willing to participate (mean (SD) age=36.1±10.4 years versus 32.8±10.9 years; p value=0.01) but similar regarding the mean family size (5.1±2.4 compared to 4.9±2.3; p value=0.4), sex distribution (60% compared to 69% were males; p value=0.1), high risk parenteral exposures in the one to six months before onset of symptoms (74% vs 70%; p value=0.5), and low risk parenteral exposures in the same period (87% vs 90%; p value=0.4). Of note, the case–control analysis of risk factors presented here includes some of the participants of another similar study performed during overlapping periods in the two fever hospitals.17 However, only 19% of cases and 27% of controls were common to the two studies, preserving the originality of the results presented here.

    Patients with acute hepatitis A (IgM anti-HAV positive) with negative anti-HCV antibodies were also asked to participate in the study as study controls.

    After providing informed consent (from one of the parents if less than 18 years of age), all participants answered orally administered standardised questionnaires covering socio-demographic characteristics, present and past health conditions, and exposure to established or potential risk factors for viral hepatitis in the 1–6 months before onset of illness or in the one to six months prior to interview date for household members. Risk factors were categorised as high-risk and low-risk parenteral exposures based on the magnitude of the associations with HCV transmission documented in previous studies.18 19 High-risk parenteral exposures included surgery, blood transfusion, haemodialysis, biopsy, endoscopy, caesarean section, episiotomy, uterine curettage, injection, infusion, catheter, sclerotherapy of varicose veins, dental care and illicit drug use (only male participants were asked, due to the sensitive nature of this question). Low risk parenteral exposures included acupuncture, shaving at barber, tattooing, pedicure, manicure and circumcision. Also assessed was exposure to other potential causes of hepatitis, including drugs, pesticides, and other chemicals known for their hepatotoxicity.

    Laboratory methods and phylogenetic study

    A 10 ml venous blood sample was collected. Patients were tested for standard liver functions (alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and indirect bilirubin, alkaline phosphatase) and for the following hepatitis markers: anti-HAV IgM (HAVAB®, M EIA; Abbott Laboratories, Diagnostics Division, Abbott park, Illinois, USA), anti-HBc IgM (CORZYME®, M rDNA; Abbott Laboratories, Diagnostics Division) and HBs antigen (AUSZYME MONOCLONAL®, third generation EIA; Abbott Laboratories, Diagnostics Division). In patients with non-A non-B hepatitis, anti-HCV antibody and HCV-RNA were assessed serologically (INNOTEST® HCV Ab IV; Innogenetics, Ghent, Belgium) and using PCR (nested reverse transcriptase PCR by in house assay using 5′-UTR primers)20 testing, respectively. In patients with positive HCV antibodies and RNA, exacerbation of chronic hepatitis C by other infectious agents was ruled out using reverse transcriptase PCR for HEV-RNA (in house assay using ORF1 and ORF2 primers) and serological testing [anti-Epstein–Barr virus (EBV) IgM (ETI-EBV-M reverse P001605; Dia Sorin, Vercelle, Italy), anti-cytomegalovirus (CMV) IgM (AXSYM® system-CMV-IgM; Abbott Laboratories, Wiesbaden, Delknheim, Germany), and anti-Toxoplasma IgM (AXSYM® system-Toxo-IgM, Abbott Laboratories, Wiesbaden, Delknheim, Germany)].

    The household members also provided a blood sample for HCV antibody and RNA testing.

    HCV sequences analysed were those of index acute hepatitis C cases and their viraemic family members. Sequence analysis included alignment, correction and homology comparison of the consensus nucleotide (330 base pairs in position 7939–8269) of the NS5B region. Of note, study sequences were deposited in the EMBL Nucleotide Sequence Database under the accession numbers FN668570 to FN668616 for the NS5b region.

    These sequences were then compared with published reference sequences (GENBANK n>30) and with isolates' sequences of local chronically infected subjects, using Clustal W program version 1.8. Distances between pairs of sequences were estimated using the MEGA program (DNADIST Kimura 2 parameters). A phylogenetic tree was then modelled using the algorithm of the ‘Neighbour-Joining’. The reliability of the structure of the branches was estimated by bootstraping (n=1000) with a minimum value of 75% to be considered reliable. The graphic output was created with DRAWGRAM included in the software PHYLIP.

    Statistical analysis

    For the comparison of exposure proportions among cases and controls, age and sex direct standardisation was used because of the different age and sex distributions among the three groups, taking the age and sex distribution of the total study population for the standard. Since the two series of controls gave very similar estimates for exposure proportions (see table 1), they were merged into one single control group for the logistic regression analysis. All putative exposures were tested for association with acute hepatitis C in ‘univariate’ analysis (with adjustment for sex and age in 2-year categories) and those with p<0.2 were then entered into a logistic regression model to examine their independent effect. Interaction terms were created for each exposure variable with sex and literacy. None were significant when introduced in the final model that was obtained through stepwise deletion of variables until all variables left in the model had p-values <0.05. Goodness of fit was assessed using the Hosmer Lemeshow statistic. The p value of the final model was >0.75, suggesting that the model fits quite well.21

    View this table:
    Table 1

    Distribution of hepatitis C virus (HCV) risk factors among acute hepatitis C cases and 678 controls, in Greater Cairo, 2002–2007

    The population attributable fractions (AFs) for each exposure (ie, the proportion of new infections due to each exposure) was estimated as the relative decline in the number of cases in the study population had nobody been exposed to that precise exposure, following the method detailed by Brady for calculating adjusted population AFs from logistic regression in STATA.22 The AFs associated with all independent iatrogenic risk factors of the final model taken together was calculated by creating a variable taking value 1 if exposed to any of the risk factors, 0 otherwise. A multiple imputation parameter model23 was used to estimate the missing values of the variable ‘gum treatment’ (n =45).

    With 100 cases and 600 controls this study had 80% power to detect odds ratios of 2.4 and higher characterising the association between exposure and HCV infection for exposures present in 10% of the control population (α=0.05; two-sided tests). Data were analysed using STATA 10.0 software.

    Results

    Case–control study

    In addition to the 100 acute hepatitis C cases, 678 controls (416 household members and 262 hepatitis A patients) were included in the case–control analysis. Acute hepatitis C patients were significantly older than controls (mean±SD age was 36.1±10.2 compared to 28.0±11.3 years old, respectively; p value<0.001). Factors significantly associated with an increased risk of HCV transmission in the age- and sex-adjusted analysis were: hospitalisation, having had surgery, having had a catheter, stitches, IV perfusion, IV injections, transfusion, caesarean section, gum treatment, anaesthesia during dental care and being illiterate (table 1). In the multivariate analysis, the factors independently associated with an increased risk of HCV and their population attributable fractions (AF) were: having had a catheter (OR=5.0, 95% CI=1.4 to 17.8; AF=6.7%), an intravenous perfusion (OR=5.8, 95% CI=2.5 to 13.3; AF=20.1%), stitches (OR=2.0, 95% CI=1.3 to 6.6; AF=10.7%), gum treatment (OR=3.7, 95% CI=1.1 to 11.9; AF=3.8%) and being illiterate (OR=2.4, 95% CI=1.4 to 4.4). The AF (95% CI) associated with all those iatrogenic risk factors taken together was 34.6% (24.3% to 43.5%).

    Phylogenetic analysis

    The 100 acute hepatitis C cases included in the study (ie, index HCV cases) had 405 household members who provided blood samples (N=100 index patients + 405 household members =505 samples) (figure 1). Thirty-one index HCV cases (31%) had at least one household member with anti-HCV antibodies and seven (7%) had two household members with anti-HCV antibodies. Eighteen (18%) had at least one HCV viraemic household member. Of note, 56% (10 out of 18) of these index HCV cases were married to a relative with chronic infection. Four (4%) had two viraemic household members. Thus, the prevalence of anti-HCV antibodies among household members living in the household of acute symptomatic HCV index patients was 9% (38 out of 405) and the prevalence of HCV RNA-positive was 5% (20 out of 405).

    Figure 1
    Figure 1

    Flow of participants in the study and their viral isolates. aSeven households had two anti-HCV(+) household members. bFour households had two RNA PCR(+) household members. cOne household had two RNA PCR(+) household members.

    The dyads/triads of samples (ie, index HCV cases and household/s member with chronic infection) could not be sequenced for six out of these 18 households, due to low virus titre or mismatch of the primers. The main characteristics of the 12 households with sequenced samples (N=25) are depicted in table 2. Their genotype and subtype distribution was the following: 4a (80%, n=20), 4o (8%, n=2), 4m (4%, n=1), 1g (4%) and 1b (4%). Out of these 12 sequenced households, 10 (83%) pairs were genotype-concordant and nine (75%) pairs had the same genotype and subtype. Three out of the initial 100 index HCV cases (households 1, 2 and 3) had highly similar sequences when compared to their chronic infected members, with more than 99% sequences homology (figure 2). None of them had any high-risk exposure in the 1–6 months preceding the onset of symptoms; living with a spouse chronically infected with HCV was the only exposure at risk.

    View this table:
    Table 2

    Main features of the index patients with genotype-concordant household members ordered by homology

    Figure 2
    Figure 2

    NS5b sequences phylogenetic tree (samples from this study and the Egyptian Genbank). The tree was constructed using the neighbour-joining method with the 25 viral isolates from the study participants, 23 chronic HCV patients also diagnosed at the fever hospitals and 29 Egyptian prototype sequences sampled from GenBank and designated by their genotype, name of isolated, country of origin and accession number. Brackets indicate the HCV genetic clusters. Numerical values on branches indicate the percentage of bootstrap replicates that support that phylogenetic split. The scale bar shows substitutions per nucleotide site. The pairs of sequences with ‘virtually identical strains’ are the following (all genotype 4a): household 1: AF02906 and AF02859 (red dots); household 2: AF02419 and AF02572 (light sky-blue dots); household 3: AF00429 and AF00983 (light emerald-green dots).

    The sequences of one additional pair (household 4) were quite similar but not enough to confirm that the transmission event took place recently since the genetic distance was higher than 2% (0.0222±0.0088 substitutions per nucleotide site). Interestingly, both the index HCV cases and his chronically infected mother received dental treatment in the 1–6 months before the index patient onset of symptoms, although it is not known whether it was at the same place and time. Assuming that the proportion of households with identical strains (3/12=25%) would be the same in the entire population of patients with viraemic household members (n=18), it is estimated that 18*25%=4.5% of all acute index patients have been infected via another household member.

    Discussion

    Since the introduction of blood donor selection and screening for HCV antibodies and RNA, intravenous drug use and invasive medical procedures are the main current risk factors for HCV transmission worldwide. However, there has been much debate regarding other HCV potential modes of transmission, particularly as a substantial proportion (more than one third) of acute HCV cases do not have a defined parenteral exposure.16 24 25 Epidemiological evidence for intra-familial transmission relies on 5- to 10-fold higher prevalence of anti-HCV positivity among household contacts compared with the general population.3 26 Most of these studies tend to overestimate the proportion of HCV infections attributable to household contact because (1) prevalence data reflect a cumulative incidence of infection over the years with no accurate relationship in time between viral exposure and the acquisition of infection, (2) of lack of exhaustive ascertainment of exposure to other potential sources of HCV, and (3) of the absence of phylogenetic analysis to confirm that anti-HCV concordant family members were infected with the same virus. This study identified three episodes of HCV intrafamilial transmission, as shown by (1) the high degree of sequence homology of their viral isolates and (2) the absence of other reported at risk exposures in the 1–6 months previous to symptoms onset, in a context of exhaustive assessment of exposures and precise identification of the timing of the events. This corresponds to less than 5% of all HCV transmissions documented in this study. Meanwhile, the case–control study based on the same HCV index cases showed that healthcare related exposures such as having had a catheter, an intravenous perfusion, stitches or gum treatment accounted for 35% of new HCV infections. Regarding iatrogenic transmission, these results are also consistent with a recent study on current risk factors for HCV transmission carried out on a different sample of the same study population.17 Thus, intrafamilial transmission is of low relative importance compared to other HCV risk factors in urban Egypt, where control of nosocomial transmission of HCV should remain the priority. Similar concerns could be raised regarding the role of intrafamilial transmission in rural areas of Egypt, particularly among children.5 In a cohort study performed in rural Egypt, we recently documented that two (11.7%) of 17 viraemic incident cases were infected by a viral strain identical to that of a household member, suggesting that intrafamilial transmission may be limited in rural settings as well.27

    Of interest, the three events of intrafamilial transmission in our study occurred within married couples and after a long duration of marriage (≥15 years). These three couples reported sharing all grooming items. Since neither frequency of sexual intercourse nor high-risk sexual practices could be ascertained in this study, conclusions on whether sexual or domestic transmission occurred cannot be drawn. Further research is needed to understand how intrafamilial transmission occurs within spouses. Data on interspousal domestic HCV transmission are scarce with only one study carried out in Taiwan showing that infected couples shared toothbrushes more frequently that uninfected couples.28 Transmission via sharing of toothbrushes is further supported by the detection of HCV RNA on toothbrushes used by hepatitis C patients29 although it does not demonstrate the infectiousness of the corresponding viruses. Similarly, epidemiological evidence for sexual transmission lacks of consistency, that is, repeated observation of the association in different populations under different circumstances. The probability of sexual transmission within heterosexual monogamous couples has been estimated between 0% and 0.6% per year.11 30–36

    Interestingly, gum treatment was associated with an increased risk of HCV. This finding was previously reported by our group in a study conducted in a rural area of Egypt.18 However, the findings reported by Arafa et al relied on a cross-sectional study comparing individuals with and without anti-HCV antibodies. Thus, dates of contamination were unknown, exposures assessment concerned long periods of time and exposures may have occurred after HCV infection. Our results, based on incident cases reinforced the hypothesis of gum treatment as a risk factor for HCV transmission. Bleeding during gum treatment is frequent. A study reported the detection of HCV RNA on instruments after dental treatment in HCV infected patients.37 Thus, the potential for contamination of the instruments is real in the context of a high HCV prevalence and inadequate sterilisation procedures.

    Our study does suffer from some limitations. One was the non-availability of some family members for blood sampling at the time of examination, whether they were absent or refused to participate in the study. If some individuals were aware of their HCV-infected status, they might have refrained from participating in the study and were not disclosed as the potential source of infection for the index case. Yet, except for older age of the index patient, the characteristics of the households participating in the study were not different from those not participating. If some (<25%) family members were missing, it might indeed be that intrafamilial transmission has been underestimated if the missing members were those who transmitted the virus to the index case of the study. Another issue was the fact that only 12 out of 18 (67%) pairs of relevant samples could be amplified and sequenced, although there is no specific reason to believe that it introduced a bias in our analysis. More problematic would be the situation where the sequence amplified differed from that transmitted to the index patient when the viraemic family member harboured a relatively diverse population of HCV variants in the form of quasi-species. For this reason, we have chosen the NS5B region which is known to be quite stable and therefore has been used in previous studies of HCV transmission.38

    In conclusion, although this study indicates that HCV intrafamilial transmission is possible, its contribution to the overall HCV transmission is very limited in urban Egypt. In contrast, iatrogenic transmission seems to account for the bulk of new HCV infections. This information is extremely relevant for a country like Egypt where many families host a chronically infected member. Currently, there are no specific recommendations for HCV-infected individuals with regard to HCV transmission to other family members, except for not sharing sharp items (eg, razors, scissors, toothbrushes, nail clippers, etc.). Based on these results, there is no justification for changing these recommendations and, indeed, public awareness should be guided to enable a supportive environment for chronic HCV infected persons. Further efforts are needed to ensure the comprehensive implementation of the national iatrogenic infection control plan reaching quality standards and full coverage of all healthcare settings including dental care facilities.

    Acknowledgments

    We are indebted to Lenaig Le Fouler for assistance with the data; Hala Mansour for monitoring the laboratory work; the clinicians and non-medical staff at Abassia and Imbaba ‘fever’ hospitals for help with patient recruitment and follow-up; and the study participants for their time and trust.

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    Footnotes

    • Funding Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS Grant numbers 1203 and 12122.101), rue de Tolbiac, 75013 Paris, France.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study was conducted with approval from the Institutional Review Board of the Egyptian Ministry of Population and Health (MoPH) and the Ethics Committee of the National Hepatology and Tropical Medicine Research Institute (NHTMRI, Egypt).

    • Provenance and peer review Not commissioned; externally peer reviewed.

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