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Casual household transmission of human immunodeficiency virus
Medical Hypotheses (1998) $1, 115-124 © Harcourt Brace & Co. Ltd 1998
Casual household transmission of human immunodeficiency virus M. RAZEL School of Education, Bar-Ilan University, Ramat-Gan, Israel 52900 (Phone: +972 3 5318444; Fax: +972 3 5353319)
Abstract m The consistent conclusion of many studies and reviews is that there is no evidence for casual household transmission of human immunodeficiency virus (HIV). The objective of this study was to analyze the evidence for casual household transmission. Data were obtained from published studies identified by computer searching, bibliographies, and consultations with experts. The analysis indicated that casual household transmission is a route of HIV transmission.
Several studies (1-8) have reviewed the research on transmission of HIV under casual household conditions, which will be called in short household transmission. Their conclusion was that there is no evidence for household transmission, and, specifically, that: sharing household facilities such as, kitchen, bath, shower, and toilet; sharing household items such as, bed, razor, toothbrush, comb, towel, clothes, eating utensils, plates, glasses, food, telephone, typewriter, computer, writing utensils; interactions with an infected individual such as, shaking hands, hugging, kissing on cheek, kissing on lips, bathing with him, sleeping with him, or giving him injections; contacts with infected individuals through mosquitoes, bedbugs and other insects; etc. - none of these leads to transmission of HIV. The concept of household transmission derives from the practical question: What risk is involved in living with an HIV-infected person? According to this practical question, and according to the use of the concept in the research literature, we propose the following definition: A casual household contact is
a contact with an infected person, that stems from sharing living quarters with him, and over which there is no complete control (as follows from the term casual). According to this definition, conditions of household transmission do not include contacts such as sexual relations or sharing a hypodermic needle, because these contacts do not happen casually. Conditions of household transmission do not include transmission through blood transfusion, or perinatal transmission, since these routes of infection do not stem from living together. Conditions of household transmission do include percutaneous and mucocutaneous contacts with infected body materials because these contacts happen uncontrollably in the household context. The purpose of this paper is to review and analyze the evidence for household transmission. Our analyses indicate that reasonable evidence for household transmission exists. We find, however, that the interpretation given to much of this evidence is faulty. We identified several biased mechanisms of interpretation. Consistent use of any one of them would
Received 14 April 1997 Accepted 13 May 1997
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116 make it impossible to find a single case of household transmission, even if household transmission occurred, while finding an unlimited number of cases in which household transmission did not occur. One or more of these interpretation mechanisms were used in each of the studies of household transmission analyzed here, with the unavoidable result that the studies concluded that there is no evidence for household transmission.
Biased interpretation mechanisms The following biased mechanisms of interpretation were discovered in the household transmission studies.
1. Deciding by majority. According to this mechanism, cases demonstrating household transmission are invalid if, in the majority of the reported cases of HIV infection, no evidence for household transmission was obtained. The application of this principle to the question of existence of household transmission is erroneous. Since, if household transmission exists, its probability is relatively small, there will be more cases of HIV infection without household transmission than with it. Finding no household transmission in a majority of HIV cases does not necessarily disprove the existence of household transmission of HIV. 2. Pos(factum exclusion of household transmission routes. According to this mechanism, absence of evidence of household transmission reinforces the assumption that such transmission does not occur through a large variety of household contacts, whereas evidence for household transmission is not perceived as consistent with the opposite assumption, that household transmission may occur through one or more of these household transmission routes. Rather than attributing the infection to any of these forms of contact, transmission is attributed to one of two alternatives: (a) Arbitrary attribution to non-household transmission. Transmission is attributed, without evidence, to one of the non-household (in the sense of non-casual) routes of transmission, such as sexual contact, or sharing hypodermic needles. According to an unbiased interpretation, if finding no evidence for transmission indicates that no transmission occurs in a variety of household contacts, then finding evidence for transmission indicates that transmission may occur through these contacts. (b) Changing terminology. Household transmission is given another name. For example, transmission
MEDICALHYPOTHESES is sometimes attributed to 'unidentified contact with infected body materials'. Since it is impossible to distinguish between 'unidentified contact with infected body materials' and household transmission, which means contact with infected body materials during casual and unidentified contacts with a person or with various household items, what we have is simply a change in terms. The change in terms results in evidence for household transmission not being recorded as such. According to an unbiased interpretation, since evidence that does not support household transmission is recorded as such, evidence that is consistent with household, transmission must also be recorded as such. 3. Pos(factum attribution to perinatal transmission. According to this mechanism, if a child who lived with his infected mother did not become infected, he is counted as a case in which household transmission did not occur, but if he did become infected, he is not counted as a case of household transmission. Rather, infection is attributed postfactum to perinatal transmission. An unbiased interpretation requires giving equal treatment to the two kinds of outcome: either provide, in all cases, relevant evidence for household transmission, or, if the child was at risk of perinatal transmission, he must be excluded from the study of household transmission whether he became infected or not.
Analysis of case studies Case 1 One case of household transmission, reported by Wahn et al (9), was of a child who was infected by a younger sibling. The closest observed contact between them was the contact of the younger sibling's saliva with the skin of the uninfected child. This occurred in an incident in which the younger sibling bit his older brother without penetrating the skin. Wahn et al concluded that the infection of Case 1 'appears to have occurred through horizontal transmission' (9, p. 694), i.e. through household transmission. This conclusion was not accepted by later investigators. For example, in their review, Gershon et al (4) criticized the validity of Case 1, arguing that 'by contrast, follow-up of 39 individuals who were bitten, with skin penetration, by an HIV-infected individual revealed no instances of transmission, casting serious doubt on the possibility raised by the report by Wahn et al of transmission through intact skin' (4, p. 646). Other studies (6,8) similarly criticized Case 1. These criticisms are based on the mechanism of deciding by majority, which application to the issue
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CASUAL HOUSEHOLD TRANSMISSION OF HIV
of existence of household transmission is erroneous. For example, assuming that the probability of household transmission is 1 in 100, there is no justification for the contention that 39 cases of non-transmission cast doubt on the validity of one report of transmission. Wahn's study thus supports the assumption that household transmission occurs. Cases 2 and 3 A second and third case of household transmission were described by the Centers for Disease Control (CDC) (1). One was a case of transmission from infant to mother. The infant, who suffered from congenital intestinal abnormality, became infected through a blood transfusion, and his mother provided the child with home nursing care. In the second case, originally reported by Grint and McEvoy (10), an AIDS patient infected a woman who provided him with home nursing care. The CDC investigators concluded that the two cases 'suggest that HTLVIII/LAV infection m a y . . , be transmitted during unprotected contact with blood or other potentially infectious body secretions or excretions in the absence of known parenteral or sexual exposure to these fluids' (1, p. 78). However, the CDC investigators rejected the evidence as (a) irrelevant to the question of household transmission and (b) invalid, stating, that '[a] the contact between the reported mother and child is not typical of the usual contact that could be expected in a family setting ... [and that] [b] seven studies involving over 350 family members of both adults and children with AIDS have not found serologic or virologic evidence of [household] transmission' (1, p. 78). The second criticism of the CDC investigators, challenging the validity of the two cases by comparing them to 350 cases in which no evidence of infection was found, is another instance of deciding by majority. As noted above, the validity of two positive cases is not refuted by the failure to find positive evidence in 350 different cases. The first criticism is based on postfactum exclusion of household transmission routes, according to which, 'providing nursing care' (4, p. 647) is considered, along with hugging and kissing, as a behavior that belongs to household transmission (4), as long as the providers of this care did not become infected. However, as soon as they become infected, they are regarded as irrelevant and 'atypical' evidence. Cases 1 and 2 are, however, not atypical. Studies of household transmission, including the seven studies cited by the CDC (1), almost always include cases which offer home nursing care, because the question of household transmission does not refer to the 'typical'
family but to families that include an AIDS patient or a carrier. An unbiased interpretation of Cases 2 and 3 is, that since we accept the evidence of the 350 cases - - which include persons who provided home nursing care - - as supporting the assumption that household transmission does not occur, we must also accept Cases 2 and 3 as supporting the assumption that household transmission occurs. The CDC investigators used a third biased interpretation mechanism, i.e. changing terminology. In a review of transmission studies, in which no evidence for household transmission was found (6), CDC investigators defined exposure to blood and other bodily fluids as part of the conditions of household transmission. This can be inferred from the following quote: 'Several of the household studies documented no HIV transmission despite the presence of household activities that might be expected to involve contact with blood or other body fluids' (6, p. 846). On the other hand, in Cases 2 and 3, in which there was evidence for transmission, contact with blood and other bodily fluids was excluded from the routes of household transmission. An unbiased interpretation of Cases 2 and 3 requires using the same definition of household transmission in cases where no infection was documented and in cases in which infection was documented. Accordingly, Cases 2 and 3 fit the definition of household transmission. Case 4 A fourth case of household transmission involved two hemophilic brothers, and was reported by the CDC (12). The older Brother 1 was found to be seropositive after having been treated with infected blood products. The younger Brother 2, who received only uninfected blood products, was found to be infected at age 4. Similarity analysis of the HIV DNA indicated that Brother 2 was infected by Brother 1. The investigators concluded that 'the details of this case ... strongly suggest that the younger child became infected through intravenous or percutaneous exposure to his brother's blood, although no specific exposure incidents were documented' (12, p. 230). The investigators noted that the mother had administered infusion treatments to the two boys in immediate succession on approximately 15 occasions and hypothesized that she could have mistakenly reused the same needle. The researchers hypothesized also that it was possible for Brother 2 to have played with his brother's used needle and injured himself. The mother did not recall any episodes of reuse of infusion equipment nor any incidents of Brother 2 playing with this equipment. The CDC investigators interpreted this case using
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postfactum exclusion of household transmission routes in combination with arbitrary attribution to non-household transmission. The CDC investigators cited reviews (4,8) according to which, household transmission studies, in which no evidence for such transmission was found, support the assumption that household transmission does not occur by any of a large variety of routes. However, when the investigators found a case of infection, they rejected the possibility that it occurred through any of these routes and instead attributed the infection to an injury with an infected needle, with no factual basis for this attribution, or, as the investigators put it: 'although no specific exposure incidents were documented' (2, p. 230). Interpreting Case 4, the CDC investigators made use also of changing terminology. CDC investigators (6) defined 'gave injections' as a kind of 'household contact' (6, p. 847; and see also 8, p. 247). In Case 4, however, infection was attributed to the administration of an injection but the investigators contended that 'the younger child was unlikely to have been infected as a result of casual household contact' (12, p. 230). That is, once the administration of injections resulted in infection, it was not considered a form of household contact anymore. The CDC investigators also used the deciding by majority principle, saying: 'the possibility of HIV transmission by casual household contact has not been documented. In addition, all other household contacts of the older brother in this case were HIVseronegative, and several studies involving a cumulative total of more than 1000 nonsexual household contacts.., have not identified evidence for transmission' (12, p. 230). The fact that the other people in the house had not become infected by the older brother and that a thousand other cases had not become infected either, does not affect the validity of a small number of cases which had become infected. In sum, according to an unbiased interpretation, Case 4 is a case of household transmission. Case 5
A fifth case was reported by Fitzgibbon et al (13). Two children who were born to two infected mothers, lived in the same house. Child 1 was diagnosed as infected at the age of 1½ years and was assumed to have acquired the infection perinataUy. Child 2 was found to be seropositive when he was 2½ years old. Molecular similarity analysis of the HIV proviral DNA of the two children, of Child 2's mother, and of control subjects indicated that Child 2's HIV was received by him not from his mother but from Child 1. It was concluded that 'the mode of transmission in
MEDICALHYPOTHESES
this case is unknown, but transmission probably resulted from an unrecognized exposure to blood' (13, p. 1840). In their interpretation of the study's findings, Fitzgibbon et al used postfactum exclusion of household transmission routes. The investigators cited various household transmission studies (e.g. 4,6,14) and accepted their conclusion that failure to find evidence for household transmission supports the assumption that household transmission does not occur by any route, including sleeping in the same bed and sharing a toothbrush. However, finding Child 2 who was infected by Child 1 after sleeping in the same bed and after sharing a toothbrush, Fitzgibbon et al did not present this as supporting the opposite assumption that household transmission occurred. Instead, they attributed the infection to blood contact, with no factual basis for doing so, or in their words: 'no exposure of Child 2 to the blood or body fluids of Child 1 was witnessed' (13, p. 1837). Attributing the infection to possible contact of 'Child 2's mucous membranes' with 'blood from Child l ' s nose, gums, or laceration' (13, p. 1840), Fitzgibbon et al also used changing terminology. An example of household transmission is transmission that occurs through the sharing of a toothbrush. However, if using a toothbrush were to cause infection, it would not be caused by the brush itself, but by contact of mucous membranes with infected materials, such as blood, on the brush. Therefore, 'an unrecognized exposure to blood ... from Child l ' s ... gums' (13, p. 1840) is indistinguishable from an unrecognized exposure to blood on a toothbrush, and is nothing but a different name for household transmission. To summarize, according to an unbiased interpretation, the study documents another case of household transmission. Case 6
A sixth case, that was reported by the CDC (15), referred to two hemophilic adolescent brothers. The older Brother 1 was found to be seropositive after he was treated with infected blood products. Since Brother l ' s diagnosis, the younger Brother 2 received only uninfected blood products. A periodical test, performed 5½ years after Brother 1 had become infected, indicated that Brother 2 also became infected. Tests of the viral DNA indicated that Brother 2 was infected by Brother 1. During the years preceding the discovery of HIV in Brother 2, the brothers did not keep a distance from each other, as shown by the fact that the brothers slept regularly in the same bed. The CDC investigators noted that it was impossible to establish how Brother 2 was
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CASUAL HOUSEHOLD TRANSMISSION OF HIV
infected, but they concluded that 'transmission most likely occurred during the reported blood contact' (15, p. 950). This referred to one occasion on which both brothers were cut and bled lightly when sharing a razor. This occurred 1½ to 3½ years before Brother 2 was found to be infected, with at least one periodical test following the sharing of the razor showing that Brother 2 had not become infected. It was also unclear whether the infected brother had used the razor before the uninfected brother, or whether the order was reversed. In the latter case, no transmission could have resulted from the incident. Probably because of the uncertainty that the transmission occurred during the sharing of the razor, the investigators also raised the possibility that the infection occurred during 'other blood contact that went unrecognized or unreported' (15, p. 950). The investigators claimed also that it was possible that the infection occurred during sexual contact between the two brothers, though the brothers denied having had sexual relations. The CDC investigators' interpretation of the study makes use of postfactum exclusion of household transmission routes, combined with both arbitrary attribution to non-household transmission and with changing terminology. The CDC investigators (15, p. 951) cited a review of household transmission studies (6; and see 5 cited in 6), according to which, household infection does not occur through sleeping together and sharing razors. However, when the CDC investigators (15) found a case in which there was sharing of bed and razor, and in which transmission occurred, they did not conclude that the findings are consistent with the conclusion that transmission may occur through these household routes. Instead, the CDC investigators attributed the infections (a) to blood contact that was identified and reported, or (b) to blood contact that was not identified and not reported, or (c) to sexual contact that was denied by the brothers. The attribution of the infection to sexual contact had no factual basis and was thus based on arbitrary attribution to non-household (i.e. non-casual) transmission. As for the attribution to the identified and reported blood contact, we note that the distinction made by the CDC investigators between household transmission, such as through sharing of a razor, on the one hand, and blood contact that occurs during the sharing of a razor, on the other hand, is nothing but a change in terminology. If transmission occurred during blood contact that was caused by the sharing of a razor, then the transmission occurred through a household contact. As for the attribution of the infection to 'other blood contact that went unrecognized or unreported' (15, p. 950), this form of trans-
mission as well is indistinguishable from household transmission, and therefore is nothing but a terminological change. An unbiased interpretation of Case 6 is, therefore, that it is a case of household transmission that occurred through one or more household contacts, such as sharing of bed and razor. Cases 7 and 8 A seventh and eighth case were reported by the CDC (16). A 5 year-old child was infected while living with his parents who had AIDS. The analysis of the child's and mother's viral DNA indicated that the child was infected by his mother. The mother suffered from purulent, exudative skin lesions all over her body. During periods when the mother's lesions were uncovered and draining, the child frequently hugged his mother and slept with her. While the mother had intermittent gingival bleeding, she sometimes shared a toothbrush with her child. The mother would sometimes pick scabs off the child's wounds and would cause them to bleed. Case 8 was a 75 year-old woman who was found to be infected 1 year after her son had died of AIDS. During his last year, the son lived in his parents' home. During his last 6 weeks, his mother provided him with care that included bathing, feeding, changing diapers, repositioning of a urinary catheter, and treatment of a gum infection. The mother did not use gloves consistently. She reported one skin contact at least with her son's feces, but did not report contact with her son's blood. The CDC investigators attributed the infections of Cases 7 and 8 to 'mucocutaneous exposures to blood or other body substances' (16, p. 347). In their Table 1 (16, p. 355), the CDC investigators attributed the infections to 'cutaneous' contact with 'blood/exudate' for Case 7 and to 'cutaneous' contact with 'body secretions and excretions, including urine and feces' for Case 8. For Case 8, the investigators assumed that there may have been blood in the son's feces, even if this blood was not apparent to the mother. In addition, it was claimed that there may have been 'other unrecognized or unrecalled exposures to her son's blood' (16, p. 354). Attributing the infection to unrecognized or unrecalled exposures to blood, lacked any factual basis. In addition, in interpreting Cases 7 and 8, the CDC investigators used postfactum exclusion of household transmission routes, combined with changing terminology. The CDC investigators accepted the evidence of the household transmission studies (e.g. 3,5,6) that household transmission does not occur through sharing of a toothbrush, hugging with an infected person, or sharing of a toilet or other 'items that could be contaminated with urine or feces' (6, p. 56).
120 However, when a case of infection was found such as Case 7, in which the mother used the child's toothbrush, and in which the child hugged his mother, or a case such as Case 8, in which there was contact with infected urine or feces, then the CDC investigators did not conclude that the evidence is compatible with the possibility of household transmission. Instead, the infection was attributed to cutaneous contact with infected body substances. However, the distinction between hugging or sharing a toothbrush or a toilet, on the one hand, and cutaneous contact with infected body substances, on the other, is nothing but a terminological distinction. A hug and a use of a toothbrush or a toilet are infecting only when they bring about contact with infected body substances. If such contact occurred in Case 7 during a hug or sharing of a toothbrush, then the transmission occurred in a household contact. The same holds for Case 8: If the infection occurred during contact with urine or feces, then it occurred during a household contact. Hence, an unbiased interpretation of Cases 7 and 8 is that these cases are compatible with the assumption that household infection may occur. In sum, there exist at least eight case studies that support the existence of household transmission of HIV.
An analysis of sample-based studies Twenty-one sample-based studies of household transmission were found. Many of the sample-based studies used postfactum attribution to perinatal transmission. According to this mechanism, children who were not infected after living with an infected mother are presented as supporting the assumption that household transmission does not occur, while children who were infected after living with an infected mother are n o t presented as supporting the opposite assumption. Instead, these cases are explained as cases of perinatal infection and are excluded from the sample. For example, one of 101 household contacts studied by Friedland et al (14), a 5 year-old child of two intravenous drug abusers, was found to be HIV positive. The mother was diagnosed as having AIDS within a year of the child's testing, i.e. when the child was 4 or 5 years old. Although it was not known whether the mother was seropositive at the time of the child's birth, the investigators concluded that the child acquired the infection perinatally and not through casual contact. The child, who was originally included in the sample consisting of persons who had no known risk of infection other than household transmission, was excluded from the sample once his infection was discovered. On
MEDICAL HYPOTHESES
the other hand, 21 children under 6 years who were not infected, were not excluded, although perinatal transmission would have been implicated had any of them been found infected. Also McDonald and Rogers (17) noted that 'discarding a case that was accepted according to the entrance criteria of a study is an arguable practice' (17, p. 258). A solution for this biased sampling procedure was proposed in 1990 by Friedland et al (5). They proposed to accept only cases that, if found infected, could not be considered perinatal cases. Specifically, they suggested to exclude all those children under 6 - - whether infected or not - - who were born to mothers who were seropositive or of unknown serological status at birth. Unfortunately, later reviews did not make use of Friedland's solution. In the present review, Friedland's solution is applied to all 17 studies which included children under 6. Results
The frequency data derived from the sample-based studies are summarized in the table. A total of 2386 cases with a risk of household transmission were reported in 21 studies. Of these, 935 cases had more probable risks, such as sexual or perinatal contact with an infected person. These cases were therefore excluded from the sample, leaving 1451 cases for which casual contact was the most probable risk. The average length of contact (weighted by the study's sample size) was 23 months (based on those studies which reported length-of-contact data). Ten infected cases were found among the 1451 cases, which amounts to 0.4 transmissions per 100 personyears of household contact. The 95% confidence interval for this rate of transmission is 0.20 to 0.66 infection per 100 years of contact. These data provide a statistically significant rejection of the null hypothesis that the probability of household transmission is zero. The findings justify the conclusion that household transmission is a possible route of HIV infection. The present summary differs from previous summaries of household transmission studies (e.g. 1-8) for two main reasons. First, Friedland's solution of postfactum attribution to perinatal transmission was applied to all studies. As a result, 175 seronegative cases were excluded from our sample. Second, the previous reviews did not include any of the four studies which reported the 10 cases of household transmission: Luzi et al (27), Mann et al (7), Pahwa et al (31), and Thomas et al (35). No reason was given for the exclusion of Luzi's study and Thomas's study. The studies may not have been known to the reviewers. Luzi's finding of one case of household
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CASUAL HOUSEHOLD TRANSMISSION OF HIV Table
F r e q u e n c y o f h o u s e h o l d t r a n s m i s s i o n in s a m p l e - b a s e d studies
Studies
Total number of cases studied
1. Berntorp (18)
36
2. Berthier (19) 3. Biberfeld (20)
70 100
4. Brettler (21)
87
5. Fischl (22)
183
6. Friedland (5,14,23)
444
7. Jason (24,25)
62
8. Kaplan (11)
18
9. Lawrence (26)
42
10. Lusher (8)
505
11. Luzi (27)
102
12. Madhok (28) 13. Mann (7)
31 204
14. Melbye (29)
35
15. Muntean (30) 16. Pahwa (31) 17. Peterman (3)
45 22 143
18. Redfield (32)
18
19. Rogers (33) 20. Romano (34)
89 125
21. Thomas (35)
25
Totals
2386
Number of cases with more probable risks
15 sexual' partners 1 child under 6 a 0 44 sexual partners 8 children under 6 a 36 sexual partners 1 child under 6 a 45 sexual partners 23 children under 6 a 2 sexually active youths 184 sexual partners 47 children under 6 7 high-risk adults 21 sexual partners 3 children under 6 a 4 hemophilic siblings 1 sexual partner 9 children under 6 4 high-risk adults 3 sexual partners 1 child under 6 a 201 sexual partners 13 children under 6 a 22 sexual partners 12 children under 6 8 high-risk adults 8 sexual partners 18 sexual partners 1 child under 6 3 due to African conditions 5 sexual partnersb 2 children under 6 a'b 0 18 children under 6 80 sexual partners 5 children under 6 a 7 sexual partners 1 child under 6 0 36 sexual partners 21 children under 6 6 high-risk adults 9 children under 6 935
Cases for whom casual contact was most probable risk
Number of infections among casual contacts
Mean length of casual contact in months
20
24
70 48
12 24
50
13
113
206
0
23
4
0
35
38
0
20
291
0
28
60
1
34
23 182
28
0
45 4 58
0 3 0
10
0
89 62
0 0
16
1
1451
10
31
16
23 c
~Estimated. The following studies noted that their sample of household contacts included children, without specifying their ages: Bemtorp et al (18), 4 children (the youngest child was 4 years old); Bibeffeld et al (20), 9 (the children were under 7); Brettler et al (21), 3; Fischl et al (22), 109 (the children were under 25); Jason et al (24), 10; Lawrence et al (26), 4; Lusher et al (8), 46 offsprings; Melbye et al (29), 6; Peterman et al (3), 19. The estimated numbers of children under 6 years were calculated based on the assumption that the children were under 19 and that they were equally distributed between 0 and 18 years (except for the three studies in which different information was provided). bMelbye et al (29) noted that there were 9 sexual partners and 11 children in the sample of 64 household members, 35 and 29 of whom lived in households of seropositive and seronegative hemophiliacs, respectively. Assuming an equal distribution of sexual partners and children in these two subsamples, an estimate of 5 sexual partners and 6 children of seropositive hemophiliacs was obtained. CWeighted average.
122 transmission has not been questioned, and will therefore be assumed to be valid. The findings of the other three studies have been given alternative interpretations. These studies are therefore discussed in the following. Mann's study. Mann et al (7) designed a study with an experimental and a comparison group. The experimental group included the non-spouse household members of 46 AIDS patients and the comparison group included the non-spouse household members of 43 uninfected patients matched with the experimental patients on variables of gender, age, and hospital from which they were chosen. The difference in frequency of infected cases between the experimental and comparison groups was not found to be statistically significant. This, of course, is no reason not to include the study in quantitative summaries of the literature, as pointed out by Glass (36) that it is the essence of research integration that many weak findings 'can add up to a strong conclusion' (36, p. 356). Gershon et al (4) did not include the study in their summary 'because of the large number of household members at risk of community-acquired HIV-1 infection in these hyperendemic regions of Africa' (4, p. 647). This was unjustified methodologically because the use of an experimental and a comparison group was designed to control for the special characteristics of the disease in Africa. The experimental design assumes that any infection-causing factor that stems from the special characteristics of the disease in Africa would have the same effect in both groups, and that any extra cases of infection in the experimental group should be attributed to household transmission. Accordingly, the number of household transmissions in Mann's study was estimated as follows. In the experimental group, 9 out of 186 cases were seropositive. Of these, one 1 year-old was deducted because of the possibility of perinatal transmission. In the comparison group, 2, or 1.6%, out of 128 cases were seropositive. This 1.6% must be attributed to the special character of AIDS in Africa, and the same percentage should be expected in the experimental group, or 0.016 × 185 = 3 cases. These 3 are deducted from the 8 remaining cases in the experimental group, leaving 5 cases, whose infection must be attributed to household transmission. Pahwa's study. Pahwa et al (31) studied the children in 10 families in which at least one of the parents was seropositive. This sample included 22 children, 18 of whom were under 6 and are excluded based on Friedland's (5) correction. Of the remaining four, three were infected and should be classified as cases of household transmission. Gershon et al (4) elimi-
MEDICALHYPOTHESES
nated this study from the sample-based studies based on a single sentence in Pahwa's paper in which it was said: 'False-positive tests and factors such as sexual child abuse and forced or voluntary intravenous drug abuse need to be definitively ruled out before considering [household] transmission' (31, p. 2305). The sentence appeared at the end of the paper, but the possibilities of false positive tests, sexual and drug abuse were not mentioned in the paper itself, which shows that these possibilities were merely theoretical. The interpretation given by Pahwa et al to their study, and accepted by Gershon et al, was thus based on postfactum exclusion of household transmission combined with arbitrary attribution to non-household transmission. Thomas's study. Three infected children were found by Thomas et al (35) in a group of 25 children of mothers with AIDS, compared with no such children in a control group of 44 children of healthy mothers. Two of the three infected children, who were 9 months old and 2 years old, respectively, when their mothers were diagnosed with AIDS, were assumed by the researchers to have been infected perinatally. The infection of the third child, a 12 year-old girl, was attributed to 'sexual molestation of the daughter by the mother's intravenous drug-using boyfriend' (35, p. 249). The boyfriend himself was not identified to the researchers and was not tested for HIV. This means that it was not known for a fact that the boyfriend was infected. In interpreting this case, the researchers thus used postfactum exclusion of household transmission routes combined with arbitrary attribution to non-household transmission. Also, one must note that the infection was not attributed to the standard transmission route of 'sexual contact', which means that there was actually no penetrative sexual contact between the girl and the mother's boyfriend. Rather, the boyfriend must have attempted to kiss, hug, undress, etc. the girl against her will or must have actually performed some of these behaviors. The investigators thus also used changing terminology, according to which, kissing, hugging, helping to dress, etc. in cases where there was no infection, are classified as household contacts (e.g. 3,5,6,34) but, in cases where there was infection, are given another name, e.g. 'sexual molestation'. Whether these contacts are voluntary or not, does not affect their epidemiological significance. In other words, if one looks only at the epidemiologically significant physical aspect of the contact, sexual molestation cannot be distinguished from household contacts. Thus, the 12 year-old infected girl must be viewed as another case of household transmission, even if it were known that the mother's boyfriend was
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CASUAL HOUSEHOLDTRANSMISSION OF HIV
infected, and that he, and not the mother, was the source of infection. To summarize, an analysis of case studies and sample-based studies shows that household transmission is an existing phenomenon and that the risk involved is about 0.4 transmissions per 100 personyears of contact. Simonds and Chanock (6) argued that the fact that 'none of the more than 200 000 cases of acquired immunodeficiency syndrome reported to the Centers for Disease Control and Prevention have been attributed to such [household] contact' (6, p. 846) contradicts the conclusion that household transmission is an existing phenomenon. However, if identification of the source of infection of the two hundred thousand cases was based on the same biased interpretation mechanisms that were analyzed in the present paper, then there was no possibility for any of these cases to have been attributed to household transmission.
References 1. Centers for Disease Control. Apparent transmission of human T-lymphotropic virus type Ill/lymphadenopathy-associated virus from a child to a mother providing health care. Morb Mortal Wkly Rep 1986; 35: 76-79. 2. Liskin L, Blackburn R, Maier J H. AIDS--A public health crisis. Pop Rep 1986; L-6: 194-228. 3. Peterman T A, Stoneburner R L, Allen J R, Jaffe H W, Curran J W. Risk of human immunodeficiency virus transmission from heterosexual adults with tlansfusion-associated infections. J Am Med Assoc 1988; 259: 55-58. 4. Gershon R R M, Vlahov D, Nelson K E. The risk of transmission of HIV through non-percutaneous, non-sexual modes--a review. AIDS 1990; 4: 645-650. 5. Friedland G H, Kahl P A, Saltzman B R et al. Additional evidence for lack of transmission of HIV infection by close interpersonal (casual) contacts. AIDS 1990; 4 : 639-644. 6. Simonds R J, Chanock S. Medical issues related to caring for human immunodeficiency virus-infected children in and out of the home. Pediatr Infect Dis J 1993; 12: 845-852. 7. Mann J M, Quinn T C, Francis H et al. Prevalence of HTLVIII/LAV in household contacts of patients with confirmed AIDS and controls in Kinshasa, Zaire. J Am Med Assoc 1986; 256: 721-724. 8. Lusher M J, Operskalski E A, Aledort L M e t al. Risk of human immunodeficiency virus type 1 infection among sexual and nonsexual household contacts of persons with congenital clotting disorders. Pediatrics 1991; 88: 242-249. 9. Wahn V, Kramer H H, Voit T, Bruster H T, Scrampical B, Scheid A. Horizontal transmission of HIV infection between two siblings. Lancet 1986; 2: 694. 10. Grint P, McEvoy M. Two associated cases of acquired immune deficiency syndrome (AIDS). Communic Dis Rep 1985; 42: 4. 11. Kaplan J E, Oleske J M, Getchell J P e t al. Evidence against transmission of human T-lymphotropic virus/lymphadenopathy-associated virus (HTLV-IIULAV) in families of children with the acquired immunodeficiency syndrome. Pediatr Infect Dis J 1985; 4: 468-471. 12. Centers for Disease Control. HIV infection in two brothers
13.
14.
15.
16. 17. 18.
19.
20.
21.
22.
23.
24.
25.
26.
27. 28. 29. 30. 31.
receiving intravenous therapy for hemophilia. Morb Mortal Wkly Rep 1992; 41: 228-231. Fitzgibbon J E, Gaur S, Frenkel L D, Laraque F, Edlin B R, Dubin D T. Transmission from one child to another of human immunodeficiency virus type 1 with zidovudine-resistance mutation. N Engl J Med 1993; 329: 1835-1841. Friedland G H, Saltzman B R, Rogers M F et al. Lack of transmission of HTLV-III/LAV infection to household contacts of patients with AIDS or AIDS-related complex with oral candidiasis. N Engl J Med 1986; 314: 344-349. Centers for Disease Control. H1V transmission between two adolescent brothers with hemophilia. Morb Mortal Wkly Rep 1993; 42: 948-951. Centers for Disease Control. Human immunodeficiency virus transmission in household settings--United States. Morb Mortal Wkly Rep 1994; 43: 347, 353-356. McDonald C T, Rogers M P. Risk of HTLV-III/LAV transmission to household contacts. N Engl J Med 1986; 315: 258. Berntorp E, Christensen P, Lindvall K. Lack of transmission of HIV to sexual and non-sexual contacts of HIV seropositive haemophiliacs following preventive information. Scand J Infect Dis 1990; 22: 279-282. Berthier A, Chamaret S, Fauchet R et al. Transmissibility of human immunodeficiency virus in haemophilic and nonhaemophilic children living in a private school in France. Lancet 1986; ii: 598-601. Biberfeld G, Bottiger B, Berntorp E et al. Transmission of HIV infection to heterosexual partners but not to household contacts of seropositive haemophiliacs. Scand J Infect Dis 1986; 18: 497-500. Brettler D B, Forsberg A D, Levine P H, Andrews C A, Baker S, Sullivan J L. Human immunodeficiency virus isolation studies and antibody testing: household contacts and sexual partners of persons with hemophilia. Arch Intern Med 1988; 148: 1299-1301. Fischl M A, Dickinson G M, Scott G B, Klimas N, Fletcher M A, Parks W. Evaluation of heterosexual partners, children, and household contacts of adults with AIDS. J Am Med Assoc 1987; 257: 640-644. Friedland G H, Saltzman B R, Rogers M F et al. Additional evidence for lack of transmission of HIV infection to household contacts of AIDS patients. III International Conference on AIDS, Washington DC, June 1987 [abstract T.P. 67]. Jason J M, McDougal J S, Dixon G e t al. HTLV-III/LAV antibody and immune status of household contacts and sexual partners of persons with hemophilia. J Am Med Assoc 1986; 255: 212-215. Jason J M, McDougal J S, Dixon G e t al. HTLV-III/LAV antibodies in contacts of hemophiliacs. J Am Med Assoc 1986; 255: 3246. Lawrence D N, Jason J M, Bouhasin J D et al. HTLV-III/LAV antibody status of spouses and household contacts assisting in home infusion of hemophilia patients. Blood 1985; 66: 703-705. Luzi G, Ensoli B, Turbessi G, Scarpati B, Aiuti F. Transmission of HTLV-III infection by heterosexual contact. Lancet 1985; ii: 1018. Madhok R, Gracie J A, Lowe G D O e t al. Lack of H1V transmission by casual contact. Lancet 1986; ii: 863. Melbye M, Ingerslev J, Biggar R J e t al. Anal intercourse as a possible factor in heterosexual transmission of HTLV-III to spouses of hemophiliacs. N Engl J Med 1985; 312: 857. Muntean W, Zenz W, Zaunschirm W, Teubel I, Heinz F X. HTLV-III antibody status in household contacts of seropositive hemophiliacs. Blood 1986; 67: 1780-1781. Pahwa S, Kaplan M, Fikrig S e t al. Spectrum of human T-cell Lyrnphotropic Virus Type 1II infection in children: recognition
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of symptomatic, asymptomatic and seronegative patients. J Am Med Assoc 1986; 255: 2299-2305. 32. Redfield R R, Markham P D, Salahuddin S Z et al. Frequent transmission of HTLV-III among spouses of patients with AIDS-related complex and AIDS. J Am Med Assoc 1985; 253: 1571-1573. 33. Rogers M F, White C R, Sanders R et al. Lack of transmission of human immunodeficiency virus from infected children to their household contacts. Pediatrics 1990; 85: 210-214. 34. Romano N, De Crescenzo L, Lupo G e t al. Main routes of
MEDICAL HYPOTHESES
transmission of human immunodeficiency virus (H1V) infection in a family setting in Palermo, Italy. Am J Epidemiol 1988; 128: 254--260. 35. Thomas P A, Lubin K, Milberg J, Reiss R, Getchell J, Enlow R. Cohort comparison study of children whose mothers have acquired immunodeficiency syndrome and children of well inner city mothers. Pediatr Infect Dis J 1987; 6: 247-251. 36. Glass G V. Integrating findings: the meta-analysis of research. Rev Res Ed 1978; 5: 351-379.
Casual household transmission of human immunodeficiency virus M. RAZEL School of Education, Bar-Ilan University, Ramat-Gan, Israel 52900 (Phone: +972 3 5318444; Fax: +972 3 5353319)
Abstract m The consistent conclusion of many studies and reviews is that there is no evidence for casual household transmission of human immunodeficiency virus (HIV). The objective of this study was to analyze the evidence for casual household transmission. Data were obtained from published studies identified by computer searching, bibliographies, and consultations with experts. The analysis indicated that casual household transmission is a route of HIV transmission.
Several studies (1-8) have reviewed the research on transmission of HIV under casual household conditions, which will be called in short household transmission. Their conclusion was that there is no evidence for household transmission, and, specifically, that: sharing household facilities such as, kitchen, bath, shower, and toilet; sharing household items such as, bed, razor, toothbrush, comb, towel, clothes, eating utensils, plates, glasses, food, telephone, typewriter, computer, writing utensils; interactions with an infected individual such as, shaking hands, hugging, kissing on cheek, kissing on lips, bathing with him, sleeping with him, or giving him injections; contacts with infected individuals through mosquitoes, bedbugs and other insects; etc. - none of these leads to transmission of HIV. The concept of household transmission derives from the practical question: What risk is involved in living with an HIV-infected person? According to this practical question, and according to the use of the concept in the research literature, we propose the following definition: A casual household contact is
a contact with an infected person, that stems from sharing living quarters with him, and over which there is no complete control (as follows from the term casual). According to this definition, conditions of household transmission do not include contacts such as sexual relations or sharing a hypodermic needle, because these contacts do not happen casually. Conditions of household transmission do not include transmission through blood transfusion, or perinatal transmission, since these routes of infection do not stem from living together. Conditions of household transmission do include percutaneous and mucocutaneous contacts with infected body materials because these contacts happen uncontrollably in the household context. The purpose of this paper is to review and analyze the evidence for household transmission. Our analyses indicate that reasonable evidence for household transmission exists. We find, however, that the interpretation given to much of this evidence is faulty. We identified several biased mechanisms of interpretation. Consistent use of any one of them would
Received 14 April 1997 Accepted 13 May 1997
115
116 make it impossible to find a single case of household transmission, even if household transmission occurred, while finding an unlimited number of cases in which household transmission did not occur. One or more of these interpretation mechanisms were used in each of the studies of household transmission analyzed here, with the unavoidable result that the studies concluded that there is no evidence for household transmission.
Biased interpretation mechanisms The following biased mechanisms of interpretation were discovered in the household transmission studies.
1. Deciding by majority. According to this mechanism, cases demonstrating household transmission are invalid if, in the majority of the reported cases of HIV infection, no evidence for household transmission was obtained. The application of this principle to the question of existence of household transmission is erroneous. Since, if household transmission exists, its probability is relatively small, there will be more cases of HIV infection without household transmission than with it. Finding no household transmission in a majority of HIV cases does not necessarily disprove the existence of household transmission of HIV. 2. Pos(factum exclusion of household transmission routes. According to this mechanism, absence of evidence of household transmission reinforces the assumption that such transmission does not occur through a large variety of household contacts, whereas evidence for household transmission is not perceived as consistent with the opposite assumption, that household transmission may occur through one or more of these household transmission routes. Rather than attributing the infection to any of these forms of contact, transmission is attributed to one of two alternatives: (a) Arbitrary attribution to non-household transmission. Transmission is attributed, without evidence, to one of the non-household (in the sense of non-casual) routes of transmission, such as sexual contact, or sharing hypodermic needles. According to an unbiased interpretation, if finding no evidence for transmission indicates that no transmission occurs in a variety of household contacts, then finding evidence for transmission indicates that transmission may occur through these contacts. (b) Changing terminology. Household transmission is given another name. For example, transmission
MEDICALHYPOTHESES is sometimes attributed to 'unidentified contact with infected body materials'. Since it is impossible to distinguish between 'unidentified contact with infected body materials' and household transmission, which means contact with infected body materials during casual and unidentified contacts with a person or with various household items, what we have is simply a change in terms. The change in terms results in evidence for household transmission not being recorded as such. According to an unbiased interpretation, since evidence that does not support household transmission is recorded as such, evidence that is consistent with household, transmission must also be recorded as such. 3. Pos(factum attribution to perinatal transmission. According to this mechanism, if a child who lived with his infected mother did not become infected, he is counted as a case in which household transmission did not occur, but if he did become infected, he is not counted as a case of household transmission. Rather, infection is attributed postfactum to perinatal transmission. An unbiased interpretation requires giving equal treatment to the two kinds of outcome: either provide, in all cases, relevant evidence for household transmission, or, if the child was at risk of perinatal transmission, he must be excluded from the study of household transmission whether he became infected or not.
Analysis of case studies Case 1 One case of household transmission, reported by Wahn et al (9), was of a child who was infected by a younger sibling. The closest observed contact between them was the contact of the younger sibling's saliva with the skin of the uninfected child. This occurred in an incident in which the younger sibling bit his older brother without penetrating the skin. Wahn et al concluded that the infection of Case 1 'appears to have occurred through horizontal transmission' (9, p. 694), i.e. through household transmission. This conclusion was not accepted by later investigators. For example, in their review, Gershon et al (4) criticized the validity of Case 1, arguing that 'by contrast, follow-up of 39 individuals who were bitten, with skin penetration, by an HIV-infected individual revealed no instances of transmission, casting serious doubt on the possibility raised by the report by Wahn et al of transmission through intact skin' (4, p. 646). Other studies (6,8) similarly criticized Case 1. These criticisms are based on the mechanism of deciding by majority, which application to the issue
117
CASUAL HOUSEHOLD TRANSMISSION OF HIV
of existence of household transmission is erroneous. For example, assuming that the probability of household transmission is 1 in 100, there is no justification for the contention that 39 cases of non-transmission cast doubt on the validity of one report of transmission. Wahn's study thus supports the assumption that household transmission occurs. Cases 2 and 3 A second and third case of household transmission were described by the Centers for Disease Control (CDC) (1). One was a case of transmission from infant to mother. The infant, who suffered from congenital intestinal abnormality, became infected through a blood transfusion, and his mother provided the child with home nursing care. In the second case, originally reported by Grint and McEvoy (10), an AIDS patient infected a woman who provided him with home nursing care. The CDC investigators concluded that the two cases 'suggest that HTLVIII/LAV infection m a y . . , be transmitted during unprotected contact with blood or other potentially infectious body secretions or excretions in the absence of known parenteral or sexual exposure to these fluids' (1, p. 78). However, the CDC investigators rejected the evidence as (a) irrelevant to the question of household transmission and (b) invalid, stating, that '[a] the contact between the reported mother and child is not typical of the usual contact that could be expected in a family setting ... [and that] [b] seven studies involving over 350 family members of both adults and children with AIDS have not found serologic or virologic evidence of [household] transmission' (1, p. 78). The second criticism of the CDC investigators, challenging the validity of the two cases by comparing them to 350 cases in which no evidence of infection was found, is another instance of deciding by majority. As noted above, the validity of two positive cases is not refuted by the failure to find positive evidence in 350 different cases. The first criticism is based on postfactum exclusion of household transmission routes, according to which, 'providing nursing care' (4, p. 647) is considered, along with hugging and kissing, as a behavior that belongs to household transmission (4), as long as the providers of this care did not become infected. However, as soon as they become infected, they are regarded as irrelevant and 'atypical' evidence. Cases 1 and 2 are, however, not atypical. Studies of household transmission, including the seven studies cited by the CDC (1), almost always include cases which offer home nursing care, because the question of household transmission does not refer to the 'typical'
family but to families that include an AIDS patient or a carrier. An unbiased interpretation of Cases 2 and 3 is, that since we accept the evidence of the 350 cases - - which include persons who provided home nursing care - - as supporting the assumption that household transmission does not occur, we must also accept Cases 2 and 3 as supporting the assumption that household transmission occurs. The CDC investigators used a third biased interpretation mechanism, i.e. changing terminology. In a review of transmission studies, in which no evidence for household transmission was found (6), CDC investigators defined exposure to blood and other bodily fluids as part of the conditions of household transmission. This can be inferred from the following quote: 'Several of the household studies documented no HIV transmission despite the presence of household activities that might be expected to involve contact with blood or other body fluids' (6, p. 846). On the other hand, in Cases 2 and 3, in which there was evidence for transmission, contact with blood and other bodily fluids was excluded from the routes of household transmission. An unbiased interpretation of Cases 2 and 3 requires using the same definition of household transmission in cases where no infection was documented and in cases in which infection was documented. Accordingly, Cases 2 and 3 fit the definition of household transmission. Case 4 A fourth case of household transmission involved two hemophilic brothers, and was reported by the CDC (12). The older Brother 1 was found to be seropositive after having been treated with infected blood products. The younger Brother 2, who received only uninfected blood products, was found to be infected at age 4. Similarity analysis of the HIV DNA indicated that Brother 2 was infected by Brother 1. The investigators concluded that 'the details of this case ... strongly suggest that the younger child became infected through intravenous or percutaneous exposure to his brother's blood, although no specific exposure incidents were documented' (12, p. 230). The investigators noted that the mother had administered infusion treatments to the two boys in immediate succession on approximately 15 occasions and hypothesized that she could have mistakenly reused the same needle. The researchers hypothesized also that it was possible for Brother 2 to have played with his brother's used needle and injured himself. The mother did not recall any episodes of reuse of infusion equipment nor any incidents of Brother 2 playing with this equipment. The CDC investigators interpreted this case using
118
postfactum exclusion of household transmission routes in combination with arbitrary attribution to non-household transmission. The CDC investigators cited reviews (4,8) according to which, household transmission studies, in which no evidence for such transmission was found, support the assumption that household transmission does not occur by any of a large variety of routes. However, when the investigators found a case of infection, they rejected the possibility that it occurred through any of these routes and instead attributed the infection to an injury with an infected needle, with no factual basis for this attribution, or, as the investigators put it: 'although no specific exposure incidents were documented' (2, p. 230). Interpreting Case 4, the CDC investigators made use also of changing terminology. CDC investigators (6) defined 'gave injections' as a kind of 'household contact' (6, p. 847; and see also 8, p. 247). In Case 4, however, infection was attributed to the administration of an injection but the investigators contended that 'the younger child was unlikely to have been infected as a result of casual household contact' (12, p. 230). That is, once the administration of injections resulted in infection, it was not considered a form of household contact anymore. The CDC investigators also used the deciding by majority principle, saying: 'the possibility of HIV transmission by casual household contact has not been documented. In addition, all other household contacts of the older brother in this case were HIVseronegative, and several studies involving a cumulative total of more than 1000 nonsexual household contacts.., have not identified evidence for transmission' (12, p. 230). The fact that the other people in the house had not become infected by the older brother and that a thousand other cases had not become infected either, does not affect the validity of a small number of cases which had become infected. In sum, according to an unbiased interpretation, Case 4 is a case of household transmission. Case 5
A fifth case was reported by Fitzgibbon et al (13). Two children who were born to two infected mothers, lived in the same house. Child 1 was diagnosed as infected at the age of 1½ years and was assumed to have acquired the infection perinataUy. Child 2 was found to be seropositive when he was 2½ years old. Molecular similarity analysis of the HIV proviral DNA of the two children, of Child 2's mother, and of control subjects indicated that Child 2's HIV was received by him not from his mother but from Child 1. It was concluded that 'the mode of transmission in
MEDICALHYPOTHESES
this case is unknown, but transmission probably resulted from an unrecognized exposure to blood' (13, p. 1840). In their interpretation of the study's findings, Fitzgibbon et al used postfactum exclusion of household transmission routes. The investigators cited various household transmission studies (e.g. 4,6,14) and accepted their conclusion that failure to find evidence for household transmission supports the assumption that household transmission does not occur by any route, including sleeping in the same bed and sharing a toothbrush. However, finding Child 2 who was infected by Child 1 after sleeping in the same bed and after sharing a toothbrush, Fitzgibbon et al did not present this as supporting the opposite assumption that household transmission occurred. Instead, they attributed the infection to blood contact, with no factual basis for doing so, or in their words: 'no exposure of Child 2 to the blood or body fluids of Child 1 was witnessed' (13, p. 1837). Attributing the infection to possible contact of 'Child 2's mucous membranes' with 'blood from Child l ' s nose, gums, or laceration' (13, p. 1840), Fitzgibbon et al also used changing terminology. An example of household transmission is transmission that occurs through the sharing of a toothbrush. However, if using a toothbrush were to cause infection, it would not be caused by the brush itself, but by contact of mucous membranes with infected materials, such as blood, on the brush. Therefore, 'an unrecognized exposure to blood ... from Child l ' s ... gums' (13, p. 1840) is indistinguishable from an unrecognized exposure to blood on a toothbrush, and is nothing but a different name for household transmission. To summarize, according to an unbiased interpretation, the study documents another case of household transmission. Case 6
A sixth case, that was reported by the CDC (15), referred to two hemophilic adolescent brothers. The older Brother 1 was found to be seropositive after he was treated with infected blood products. Since Brother l ' s diagnosis, the younger Brother 2 received only uninfected blood products. A periodical test, performed 5½ years after Brother 1 had become infected, indicated that Brother 2 also became infected. Tests of the viral DNA indicated that Brother 2 was infected by Brother 1. During the years preceding the discovery of HIV in Brother 2, the brothers did not keep a distance from each other, as shown by the fact that the brothers slept regularly in the same bed. The CDC investigators noted that it was impossible to establish how Brother 2 was
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CASUAL HOUSEHOLD TRANSMISSION OF HIV
infected, but they concluded that 'transmission most likely occurred during the reported blood contact' (15, p. 950). This referred to one occasion on which both brothers were cut and bled lightly when sharing a razor. This occurred 1½ to 3½ years before Brother 2 was found to be infected, with at least one periodical test following the sharing of the razor showing that Brother 2 had not become infected. It was also unclear whether the infected brother had used the razor before the uninfected brother, or whether the order was reversed. In the latter case, no transmission could have resulted from the incident. Probably because of the uncertainty that the transmission occurred during the sharing of the razor, the investigators also raised the possibility that the infection occurred during 'other blood contact that went unrecognized or unreported' (15, p. 950). The investigators claimed also that it was possible that the infection occurred during sexual contact between the two brothers, though the brothers denied having had sexual relations. The CDC investigators' interpretation of the study makes use of postfactum exclusion of household transmission routes, combined with both arbitrary attribution to non-household transmission and with changing terminology. The CDC investigators (15, p. 951) cited a review of household transmission studies (6; and see 5 cited in 6), according to which, household infection does not occur through sleeping together and sharing razors. However, when the CDC investigators (15) found a case in which there was sharing of bed and razor, and in which transmission occurred, they did not conclude that the findings are consistent with the conclusion that transmission may occur through these household routes. Instead, the CDC investigators attributed the infections (a) to blood contact that was identified and reported, or (b) to blood contact that was not identified and not reported, or (c) to sexual contact that was denied by the brothers. The attribution of the infection to sexual contact had no factual basis and was thus based on arbitrary attribution to non-household (i.e. non-casual) transmission. As for the attribution to the identified and reported blood contact, we note that the distinction made by the CDC investigators between household transmission, such as through sharing of a razor, on the one hand, and blood contact that occurs during the sharing of a razor, on the other hand, is nothing but a change in terminology. If transmission occurred during blood contact that was caused by the sharing of a razor, then the transmission occurred through a household contact. As for the attribution of the infection to 'other blood contact that went unrecognized or unreported' (15, p. 950), this form of trans-
mission as well is indistinguishable from household transmission, and therefore is nothing but a terminological change. An unbiased interpretation of Case 6 is, therefore, that it is a case of household transmission that occurred through one or more household contacts, such as sharing of bed and razor. Cases 7 and 8 A seventh and eighth case were reported by the CDC (16). A 5 year-old child was infected while living with his parents who had AIDS. The analysis of the child's and mother's viral DNA indicated that the child was infected by his mother. The mother suffered from purulent, exudative skin lesions all over her body. During periods when the mother's lesions were uncovered and draining, the child frequently hugged his mother and slept with her. While the mother had intermittent gingival bleeding, she sometimes shared a toothbrush with her child. The mother would sometimes pick scabs off the child's wounds and would cause them to bleed. Case 8 was a 75 year-old woman who was found to be infected 1 year after her son had died of AIDS. During his last year, the son lived in his parents' home. During his last 6 weeks, his mother provided him with care that included bathing, feeding, changing diapers, repositioning of a urinary catheter, and treatment of a gum infection. The mother did not use gloves consistently. She reported one skin contact at least with her son's feces, but did not report contact with her son's blood. The CDC investigators attributed the infections of Cases 7 and 8 to 'mucocutaneous exposures to blood or other body substances' (16, p. 347). In their Table 1 (16, p. 355), the CDC investigators attributed the infections to 'cutaneous' contact with 'blood/exudate' for Case 7 and to 'cutaneous' contact with 'body secretions and excretions, including urine and feces' for Case 8. For Case 8, the investigators assumed that there may have been blood in the son's feces, even if this blood was not apparent to the mother. In addition, it was claimed that there may have been 'other unrecognized or unrecalled exposures to her son's blood' (16, p. 354). Attributing the infection to unrecognized or unrecalled exposures to blood, lacked any factual basis. In addition, in interpreting Cases 7 and 8, the CDC investigators used postfactum exclusion of household transmission routes, combined with changing terminology. The CDC investigators accepted the evidence of the household transmission studies (e.g. 3,5,6) that household transmission does not occur through sharing of a toothbrush, hugging with an infected person, or sharing of a toilet or other 'items that could be contaminated with urine or feces' (6, p. 56).
120 However, when a case of infection was found such as Case 7, in which the mother used the child's toothbrush, and in which the child hugged his mother, or a case such as Case 8, in which there was contact with infected urine or feces, then the CDC investigators did not conclude that the evidence is compatible with the possibility of household transmission. Instead, the infection was attributed to cutaneous contact with infected body substances. However, the distinction between hugging or sharing a toothbrush or a toilet, on the one hand, and cutaneous contact with infected body substances, on the other, is nothing but a terminological distinction. A hug and a use of a toothbrush or a toilet are infecting only when they bring about contact with infected body substances. If such contact occurred in Case 7 during a hug or sharing of a toothbrush, then the transmission occurred in a household contact. The same holds for Case 8: If the infection occurred during contact with urine or feces, then it occurred during a household contact. Hence, an unbiased interpretation of Cases 7 and 8 is that these cases are compatible with the assumption that household infection may occur. In sum, there exist at least eight case studies that support the existence of household transmission of HIV.
An analysis of sample-based studies Twenty-one sample-based studies of household transmission were found. Many of the sample-based studies used postfactum attribution to perinatal transmission. According to this mechanism, children who were not infected after living with an infected mother are presented as supporting the assumption that household transmission does not occur, while children who were infected after living with an infected mother are n o t presented as supporting the opposite assumption. Instead, these cases are explained as cases of perinatal infection and are excluded from the sample. For example, one of 101 household contacts studied by Friedland et al (14), a 5 year-old child of two intravenous drug abusers, was found to be HIV positive. The mother was diagnosed as having AIDS within a year of the child's testing, i.e. when the child was 4 or 5 years old. Although it was not known whether the mother was seropositive at the time of the child's birth, the investigators concluded that the child acquired the infection perinatally and not through casual contact. The child, who was originally included in the sample consisting of persons who had no known risk of infection other than household transmission, was excluded from the sample once his infection was discovered. On
MEDICAL HYPOTHESES
the other hand, 21 children under 6 years who were not infected, were not excluded, although perinatal transmission would have been implicated had any of them been found infected. Also McDonald and Rogers (17) noted that 'discarding a case that was accepted according to the entrance criteria of a study is an arguable practice' (17, p. 258). A solution for this biased sampling procedure was proposed in 1990 by Friedland et al (5). They proposed to accept only cases that, if found infected, could not be considered perinatal cases. Specifically, they suggested to exclude all those children under 6 - - whether infected or not - - who were born to mothers who were seropositive or of unknown serological status at birth. Unfortunately, later reviews did not make use of Friedland's solution. In the present review, Friedland's solution is applied to all 17 studies which included children under 6. Results
The frequency data derived from the sample-based studies are summarized in the table. A total of 2386 cases with a risk of household transmission were reported in 21 studies. Of these, 935 cases had more probable risks, such as sexual or perinatal contact with an infected person. These cases were therefore excluded from the sample, leaving 1451 cases for which casual contact was the most probable risk. The average length of contact (weighted by the study's sample size) was 23 months (based on those studies which reported length-of-contact data). Ten infected cases were found among the 1451 cases, which amounts to 0.4 transmissions per 100 personyears of household contact. The 95% confidence interval for this rate of transmission is 0.20 to 0.66 infection per 100 years of contact. These data provide a statistically significant rejection of the null hypothesis that the probability of household transmission is zero. The findings justify the conclusion that household transmission is a possible route of HIV infection. The present summary differs from previous summaries of household transmission studies (e.g. 1-8) for two main reasons. First, Friedland's solution of postfactum attribution to perinatal transmission was applied to all studies. As a result, 175 seronegative cases were excluded from our sample. Second, the previous reviews did not include any of the four studies which reported the 10 cases of household transmission: Luzi et al (27), Mann et al (7), Pahwa et al (31), and Thomas et al (35). No reason was given for the exclusion of Luzi's study and Thomas's study. The studies may not have been known to the reviewers. Luzi's finding of one case of household
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CASUAL HOUSEHOLD TRANSMISSION OF HIV Table
F r e q u e n c y o f h o u s e h o l d t r a n s m i s s i o n in s a m p l e - b a s e d studies
Studies
Total number of cases studied
1. Berntorp (18)
36
2. Berthier (19) 3. Biberfeld (20)
70 100
4. Brettler (21)
87
5. Fischl (22)
183
6. Friedland (5,14,23)
444
7. Jason (24,25)
62
8. Kaplan (11)
18
9. Lawrence (26)
42
10. Lusher (8)
505
11. Luzi (27)
102
12. Madhok (28) 13. Mann (7)
31 204
14. Melbye (29)
35
15. Muntean (30) 16. Pahwa (31) 17. Peterman (3)
45 22 143
18. Redfield (32)
18
19. Rogers (33) 20. Romano (34)
89 125
21. Thomas (35)
25
Totals
2386
Number of cases with more probable risks
15 sexual' partners 1 child under 6 a 0 44 sexual partners 8 children under 6 a 36 sexual partners 1 child under 6 a 45 sexual partners 23 children under 6 a 2 sexually active youths 184 sexual partners 47 children under 6 7 high-risk adults 21 sexual partners 3 children under 6 a 4 hemophilic siblings 1 sexual partner 9 children under 6 4 high-risk adults 3 sexual partners 1 child under 6 a 201 sexual partners 13 children under 6 a 22 sexual partners 12 children under 6 8 high-risk adults 8 sexual partners 18 sexual partners 1 child under 6 3 due to African conditions 5 sexual partnersb 2 children under 6 a'b 0 18 children under 6 80 sexual partners 5 children under 6 a 7 sexual partners 1 child under 6 0 36 sexual partners 21 children under 6 6 high-risk adults 9 children under 6 935
Cases for whom casual contact was most probable risk
Number of infections among casual contacts
Mean length of casual contact in months
20
24
70 48
12 24
50
13
113
206
0
23
4
0
35
38
0
20
291
0
28
60
1
34
23 182
28
0
45 4 58
0 3 0
10
0
89 62
0 0
16
1
1451
10
31
16
23 c
~Estimated. The following studies noted that their sample of household contacts included children, without specifying their ages: Bemtorp et al (18), 4 children (the youngest child was 4 years old); Bibeffeld et al (20), 9 (the children were under 7); Brettler et al (21), 3; Fischl et al (22), 109 (the children were under 25); Jason et al (24), 10; Lawrence et al (26), 4; Lusher et al (8), 46 offsprings; Melbye et al (29), 6; Peterman et al (3), 19. The estimated numbers of children under 6 years were calculated based on the assumption that the children were under 19 and that they were equally distributed between 0 and 18 years (except for the three studies in which different information was provided). bMelbye et al (29) noted that there were 9 sexual partners and 11 children in the sample of 64 household members, 35 and 29 of whom lived in households of seropositive and seronegative hemophiliacs, respectively. Assuming an equal distribution of sexual partners and children in these two subsamples, an estimate of 5 sexual partners and 6 children of seropositive hemophiliacs was obtained. CWeighted average.
122 transmission has not been questioned, and will therefore be assumed to be valid. The findings of the other three studies have been given alternative interpretations. These studies are therefore discussed in the following. Mann's study. Mann et al (7) designed a study with an experimental and a comparison group. The experimental group included the non-spouse household members of 46 AIDS patients and the comparison group included the non-spouse household members of 43 uninfected patients matched with the experimental patients on variables of gender, age, and hospital from which they were chosen. The difference in frequency of infected cases between the experimental and comparison groups was not found to be statistically significant. This, of course, is no reason not to include the study in quantitative summaries of the literature, as pointed out by Glass (36) that it is the essence of research integration that many weak findings 'can add up to a strong conclusion' (36, p. 356). Gershon et al (4) did not include the study in their summary 'because of the large number of household members at risk of community-acquired HIV-1 infection in these hyperendemic regions of Africa' (4, p. 647). This was unjustified methodologically because the use of an experimental and a comparison group was designed to control for the special characteristics of the disease in Africa. The experimental design assumes that any infection-causing factor that stems from the special characteristics of the disease in Africa would have the same effect in both groups, and that any extra cases of infection in the experimental group should be attributed to household transmission. Accordingly, the number of household transmissions in Mann's study was estimated as follows. In the experimental group, 9 out of 186 cases were seropositive. Of these, one 1 year-old was deducted because of the possibility of perinatal transmission. In the comparison group, 2, or 1.6%, out of 128 cases were seropositive. This 1.6% must be attributed to the special character of AIDS in Africa, and the same percentage should be expected in the experimental group, or 0.016 × 185 = 3 cases. These 3 are deducted from the 8 remaining cases in the experimental group, leaving 5 cases, whose infection must be attributed to household transmission. Pahwa's study. Pahwa et al (31) studied the children in 10 families in which at least one of the parents was seropositive. This sample included 22 children, 18 of whom were under 6 and are excluded based on Friedland's (5) correction. Of the remaining four, three were infected and should be classified as cases of household transmission. Gershon et al (4) elimi-
MEDICALHYPOTHESES
nated this study from the sample-based studies based on a single sentence in Pahwa's paper in which it was said: 'False-positive tests and factors such as sexual child abuse and forced or voluntary intravenous drug abuse need to be definitively ruled out before considering [household] transmission' (31, p. 2305). The sentence appeared at the end of the paper, but the possibilities of false positive tests, sexual and drug abuse were not mentioned in the paper itself, which shows that these possibilities were merely theoretical. The interpretation given by Pahwa et al to their study, and accepted by Gershon et al, was thus based on postfactum exclusion of household transmission combined with arbitrary attribution to non-household transmission. Thomas's study. Three infected children were found by Thomas et al (35) in a group of 25 children of mothers with AIDS, compared with no such children in a control group of 44 children of healthy mothers. Two of the three infected children, who were 9 months old and 2 years old, respectively, when their mothers were diagnosed with AIDS, were assumed by the researchers to have been infected perinatally. The infection of the third child, a 12 year-old girl, was attributed to 'sexual molestation of the daughter by the mother's intravenous drug-using boyfriend' (35, p. 249). The boyfriend himself was not identified to the researchers and was not tested for HIV. This means that it was not known for a fact that the boyfriend was infected. In interpreting this case, the researchers thus used postfactum exclusion of household transmission routes combined with arbitrary attribution to non-household transmission. Also, one must note that the infection was not attributed to the standard transmission route of 'sexual contact', which means that there was actually no penetrative sexual contact between the girl and the mother's boyfriend. Rather, the boyfriend must have attempted to kiss, hug, undress, etc. the girl against her will or must have actually performed some of these behaviors. The investigators thus also used changing terminology, according to which, kissing, hugging, helping to dress, etc. in cases where there was no infection, are classified as household contacts (e.g. 3,5,6,34) but, in cases where there was infection, are given another name, e.g. 'sexual molestation'. Whether these contacts are voluntary or not, does not affect their epidemiological significance. In other words, if one looks only at the epidemiologically significant physical aspect of the contact, sexual molestation cannot be distinguished from household contacts. Thus, the 12 year-old infected girl must be viewed as another case of household transmission, even if it were known that the mother's boyfriend was
123
CASUAL HOUSEHOLDTRANSMISSION OF HIV
infected, and that he, and not the mother, was the source of infection. To summarize, an analysis of case studies and sample-based studies shows that household transmission is an existing phenomenon and that the risk involved is about 0.4 transmissions per 100 personyears of contact. Simonds and Chanock (6) argued that the fact that 'none of the more than 200 000 cases of acquired immunodeficiency syndrome reported to the Centers for Disease Control and Prevention have been attributed to such [household] contact' (6, p. 846) contradicts the conclusion that household transmission is an existing phenomenon. However, if identification of the source of infection of the two hundred thousand cases was based on the same biased interpretation mechanisms that were analyzed in the present paper, then there was no possibility for any of these cases to have been attributed to household transmission.
References 1. Centers for Disease Control. Apparent transmission of human T-lymphotropic virus type Ill/lymphadenopathy-associated virus from a child to a mother providing health care. Morb Mortal Wkly Rep 1986; 35: 76-79. 2. Liskin L, Blackburn R, Maier J H. AIDS--A public health crisis. Pop Rep 1986; L-6: 194-228. 3. Peterman T A, Stoneburner R L, Allen J R, Jaffe H W, Curran J W. Risk of human immunodeficiency virus transmission from heterosexual adults with tlansfusion-associated infections. J Am Med Assoc 1988; 259: 55-58. 4. Gershon R R M, Vlahov D, Nelson K E. The risk of transmission of HIV through non-percutaneous, non-sexual modes--a review. AIDS 1990; 4: 645-650. 5. Friedland G H, Kahl P A, Saltzman B R et al. Additional evidence for lack of transmission of HIV infection by close interpersonal (casual) contacts. AIDS 1990; 4 : 639-644. 6. Simonds R J, Chanock S. Medical issues related to caring for human immunodeficiency virus-infected children in and out of the home. Pediatr Infect Dis J 1993; 12: 845-852. 7. Mann J M, Quinn T C, Francis H et al. Prevalence of HTLVIII/LAV in household contacts of patients with confirmed AIDS and controls in Kinshasa, Zaire. J Am Med Assoc 1986; 256: 721-724. 8. Lusher M J, Operskalski E A, Aledort L M e t al. Risk of human immunodeficiency virus type 1 infection among sexual and nonsexual household contacts of persons with congenital clotting disorders. Pediatrics 1991; 88: 242-249. 9. Wahn V, Kramer H H, Voit T, Bruster H T, Scrampical B, Scheid A. Horizontal transmission of HIV infection between two siblings. Lancet 1986; 2: 694. 10. Grint P, McEvoy M. Two associated cases of acquired immune deficiency syndrome (AIDS). Communic Dis Rep 1985; 42: 4. 11. Kaplan J E, Oleske J M, Getchell J P e t al. Evidence against transmission of human T-lymphotropic virus/lymphadenopathy-associated virus (HTLV-IIULAV) in families of children with the acquired immunodeficiency syndrome. Pediatr Infect Dis J 1985; 4: 468-471. 12. Centers for Disease Control. HIV infection in two brothers
13.
14.
15.
16. 17. 18.
19.
20.
21.
22.
23.
24.
25.
26.
27. 28. 29. 30. 31.
receiving intravenous therapy for hemophilia. Morb Mortal Wkly Rep 1992; 41: 228-231. Fitzgibbon J E, Gaur S, Frenkel L D, Laraque F, Edlin B R, Dubin D T. Transmission from one child to another of human immunodeficiency virus type 1 with zidovudine-resistance mutation. N Engl J Med 1993; 329: 1835-1841. Friedland G H, Saltzman B R, Rogers M F et al. Lack of transmission of HTLV-III/LAV infection to household contacts of patients with AIDS or AIDS-related complex with oral candidiasis. N Engl J Med 1986; 314: 344-349. Centers for Disease Control. H1V transmission between two adolescent brothers with hemophilia. Morb Mortal Wkly Rep 1993; 42: 948-951. Centers for Disease Control. Human immunodeficiency virus transmission in household settings--United States. Morb Mortal Wkly Rep 1994; 43: 347, 353-356. McDonald C T, Rogers M P. Risk of HTLV-III/LAV transmission to household contacts. N Engl J Med 1986; 315: 258. Berntorp E, Christensen P, Lindvall K. Lack of transmission of HIV to sexual and non-sexual contacts of HIV seropositive haemophiliacs following preventive information. Scand J Infect Dis 1990; 22: 279-282. Berthier A, Chamaret S, Fauchet R et al. Transmissibility of human immunodeficiency virus in haemophilic and nonhaemophilic children living in a private school in France. Lancet 1986; ii: 598-601. Biberfeld G, Bottiger B, Berntorp E et al. Transmission of HIV infection to heterosexual partners but not to household contacts of seropositive haemophiliacs. Scand J Infect Dis 1986; 18: 497-500. Brettler D B, Forsberg A D, Levine P H, Andrews C A, Baker S, Sullivan J L. Human immunodeficiency virus isolation studies and antibody testing: household contacts and sexual partners of persons with hemophilia. Arch Intern Med 1988; 148: 1299-1301. Fischl M A, Dickinson G M, Scott G B, Klimas N, Fletcher M A, Parks W. Evaluation of heterosexual partners, children, and household contacts of adults with AIDS. J Am Med Assoc 1987; 257: 640-644. Friedland G H, Saltzman B R, Rogers M F et al. Additional evidence for lack of transmission of HIV infection to household contacts of AIDS patients. III International Conference on AIDS, Washington DC, June 1987 [abstract T.P. 67]. Jason J M, McDougal J S, Dixon G e t al. HTLV-III/LAV antibody and immune status of household contacts and sexual partners of persons with hemophilia. J Am Med Assoc 1986; 255: 212-215. Jason J M, McDougal J S, Dixon G e t al. HTLV-III/LAV antibodies in contacts of hemophiliacs. J Am Med Assoc 1986; 255: 3246. Lawrence D N, Jason J M, Bouhasin J D et al. HTLV-III/LAV antibody status of spouses and household contacts assisting in home infusion of hemophilia patients. Blood 1985; 66: 703-705. Luzi G, Ensoli B, Turbessi G, Scarpati B, Aiuti F. Transmission of HTLV-III infection by heterosexual contact. Lancet 1985; ii: 1018. Madhok R, Gracie J A, Lowe G D O e t al. Lack of H1V transmission by casual contact. Lancet 1986; ii: 863. Melbye M, Ingerslev J, Biggar R J e t al. Anal intercourse as a possible factor in heterosexual transmission of HTLV-III to spouses of hemophiliacs. N Engl J Med 1985; 312: 857. Muntean W, Zenz W, Zaunschirm W, Teubel I, Heinz F X. HTLV-III antibody status in household contacts of seropositive hemophiliacs. Blood 1986; 67: 1780-1781. Pahwa S, Kaplan M, Fikrig S e t al. Spectrum of human T-cell Lyrnphotropic Virus Type 1II infection in children: recognition
124
of symptomatic, asymptomatic and seronegative patients. J Am Med Assoc 1986; 255: 2299-2305. 32. Redfield R R, Markham P D, Salahuddin S Z et al. Frequent transmission of HTLV-III among spouses of patients with AIDS-related complex and AIDS. J Am Med Assoc 1985; 253: 1571-1573. 33. Rogers M F, White C R, Sanders R et al. Lack of transmission of human immunodeficiency virus from infected children to their household contacts. Pediatrics 1990; 85: 210-214. 34. Romano N, De Crescenzo L, Lupo G e t al. Main routes of
MEDICAL HYPOTHESES
transmission of human immunodeficiency virus (H1V) infection in a family setting in Palermo, Italy. Am J Epidemiol 1988; 128: 254--260. 35. Thomas P A, Lubin K, Milberg J, Reiss R, Getchell J, Enlow R. Cohort comparison study of children whose mothers have acquired immunodeficiency syndrome and children of well inner city mothers. Pediatr Infect Dis J 1987; 6: 247-251. 36. Glass G V. Integrating findings: the meta-analysis of research. Rev Res Ed 1978; 5: 351-379.