Rabies

Abstract

Readers are invited to use this article as a self-assessment exercise and to update their knowledge. A 6-year-old girl in West Africa was attacked and bitten on the left ear by a dog in a market. As rabies was suspected, the dog was killed. The child suffered lacerations of the ear and abrasion of the adjacent scalp area. Her wounds were treated with an antiseptic solution and bandaged up. No rabies vaccine was available in the village. Four days later she presented at a Mission hospital 50 miles away. The wounds were cleaned with povidone iodine, and sutured. An intramuscular dose of a European cell culture rabies vaccine was given into the deltoid, and repeated 3 and 14 days later. Rabies immune globulin (RIG) was not given. Twenty-three days after the bite the girl developed a fever, hypersalivation and restlessness. Dysphagia, aerophobia and coma ensued, and she died of presumed rabies encephalitis 2 days later. Many of the difficulties of rabies prophylaxis are demonstrated here. Although the people in the village knew that rabies vaccine was needed for the child, information about wound cleaning was inadequate. Thorough washing or scrubbing with copious soap or detergent and water can reduce the chance of infection. The lipid-containing viral envelope is disrupted by soap. Iodine or >40% alcohol solutions may enhance the protection, and the wound should be left exposed to dry. Suturing should be avoided or delayed as virus may be inoculated deeper into the tissues [1World Health OrganizationExpert Committee on Rabies Eighth Report. Technical Report Series 824. WHO, Geneva1992Google Scholar]. The decision to use rabies prophylaxis rested on knowledge of the local epidemiology of rabies, the aggressive behavior of the animal, and the severity of the wounds. Testing the brain of the biting animal is helpful, but is rarely possible in rural areas. In any case, treatment should not be delayed while results are awaited. Vaccine can be given and the course stopped if appropriate laboratory tests prove negative. The treatment was started late. Ideally, post-exposure therapy is started on the day of the bite, and any delay increases the chance of virus entering a nerve ending. A potent vaccine was given intramuscularly using the standard regimen, but a dose on day 7 was missed. There has been no evidence of loss of potency of the lyophilized European cell-culture vaccines (see below) despite lapses in the cold chain. RIG is recommended for all people exposed to rabies, and is especially important for those with lesions on the head, neck or hands and multiple bites [1World Health OrganizationExpert Committee on Rabies Eighth Report. Technical Report Series 824. WHO, Geneva1992Google Scholar,2Fathi M Sabeti A Bahmanyar M. Séroprophylaxie anti-rabique chez les sujets mordus par loups enragés en Iran.Acta Med Iran. 1970; 13: 5-9Google Scholar], but is frequently not available. In Africa and Asia, only 1% of vaccinees received RIG in 1993 [3WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. 1997; (WHO/EMC/ZOO.96.6)Google Scholar]. To summarize, there was failure to apply all three parts of post-exposure treatment. Immediate wound care was inadequate, vaccine was begun late and the course was incomplete, and RIG was omitted. Once symptoms of encephalitis have started, sedation is all that can be offered, although there may be a role for intensive care in some circumstances (see below). In each of the numbered questions, at least one, and up to four, of the individual entries are correct. (The answers are at the end of this article.) 1Tabled 1a)Is unnecessary for a patient licked on the leg by a proven rabid dogTrue/Falseb)Is effective if given before the virus reaches the brainTrue/Falsec)Should be given even if the patient presents 4 months after being bitten by a stray dog in IndiaTrue/Falsed)Prevents death in up to 90% of patients with proven exposure to rabid animalsTrue/Falsee)Is unnecessary if the biting animal has been vaccinated against rabiesTrue/False Open table in a new tab 2Tabled 1a)Semple (sheep brain) and suckling mouse brain vaccines are no longer usedTrue/Falseb)Rabies vaccine should ideally be given pre-exposure to all residents of countries where dog rabies is endemicTrue/Falsec)The standard post-exposure course of cell culture rabies vaccines is one dose intramuscularly on days 0, 3, 7, 14 and 28True/Falsed)Economic intradermal regimens are not safe for post-exposure useTrue/Falsee)Post-exposure treatment can be stopped if the biting dog remains healthy for 10 daysTrue/False Open table in a new tab 3Tabled 1a)Either equine or human RIG should be given in one dose at the start of every post-exposure vaccine courseTrue/Falseb)The whole dose should be injected into and around the wound, if anatomically possibleTrue/Falsec)RIG treatment is always associated with a risk of serum sicknessTrue/Falsed)Pre-treatment intradermal skin testing is not necessaryTrue/Falsee)RIG neutralizes rabies virus in a wound and probably enhances the immune response to vaccineTrue/False Open table in a new tab 4Tabled 1a)May present with diarrhea and feverTrue/Falseb)Often complain of itching at the site of an animal biteTrue/Falsec)May attempt to bite other peopleTrue/Falsed)May be misdiagnosed as having tetanusTrue/Falsee)Have no chance of recoveryTrue/False Open table in a new tab 5Tabled 1a)The diagnosis cannot be made during the incubation periodTrue/Falseb)The diagnosis is usually made on clinical evidenceTrue/Falsec)The diagnosis can be confirmed during life by isolation of virus from blood, tears, respiratory secretions and cerebrospinal fluidTrue/Falsed)A rapid method of antigen detection in skin biopsies has a high rate of false-positive resultsTrue/Falsee)Confirmation of the diagnosis after death requires a full post-mortem examinationTrue/False Open table in a new tab 6Tabled 1a)Killing all stray dogs in tropical endemic areasTrue/Falseb)Vaccinating foxes in Europe by distributing live virus, in chicken heads or sausage baits, over the countrysideTrue/Falsec)Distributing oral vaccine in baits for dogsTrue/Falsed)Vaccinating raccoons and coyotes in the USATrue/Falsee)Injecting cattle with anticoagulant to reduce rabies transmission by vampire batsTrue/False Open table in a new tab 7Tabled 1a)Are rabies-related viruses, distinct from classical street rabies virusTrue/Falseb)Are the only rabies-related viruses to have caused human deathsTrue/Falsec)Have occasionally been found in terrestrial animal speciesTrue/Falsed)Are also found in North AmericaTrue/Falsee)Are susceptible to the immune response induced by cell-culture rabies vaccinesTrue/False Open table in a new tab Post-exposure prophylaxis is not only expensive but carries a burden of anxiety during the months of the possible incubation period. Patients without any risk of rabies encephalitis should not be treated, and intact skin is a barrier against infection. An abrasion made by the teeth of a suspected rabid animal, or contamination of an existing wound by the animal's saliva does represent a risk, and so does contamination of intact mucosa. The virus in a wound may first replicate in muscle or enter a motor or sensory nerve ending directly, and ascends in the axoplasm of peripheral nerves towards the brain [4Tsiang H. Pathophysiology of rabies virus infection of the nervous system.Adv Virol Res. 1993; 42: 375-412Crossref PubMed Scopus (64) Google Scholar]. No virions are detectable at this stage, and it is thought that infection is transmitted by subviral particles, perhaps as naked nucleocapsids [5Gosztonyi G Dietzschold B Kao M et al.Rabies and Borna disease. A comparative pathogenetic study of two neuro-virulent agents.Lab Invest. 1993; 68: 285-295PubMed Google Scholar]. Once inside a neuron, the virus is inaccessible to immune attack, but infection can be prevented experimentally by cutting the appropriate peripheral nerve. When the infection reaches the brain massive intracellular viral replication occurs, Negri bodies form, clinical signs appear and there is evidence of neuronal dysfunction with few if any pathologic changes [4Tsiang H. Pathophysiology of rabies virus infection of the nervous system.Adv Virol Res. 1993; 42: 375-412Crossref PubMed Scopus (64) Google Scholar,6Charlton KM. The pathogenesis of rabies and other lyssaviral infections: recent studies.in: Rupprecht CE Dietzschold B Koprowski H Lyssaviruses. Springer-Verlag, Berlin1994: 95-119Crossref Scopus (55) Google Scholar]. The virus descends back down nerves to infect many tissues, including the salivary glands where replication occurs on plasma membranes producing extracellular virus [6Charlton KM. The pathogenesis of rabies and other lyssaviral infections: recent studies.in: Rupprecht CE Dietzschold B Koprowski H Lyssaviruses. Springer-Verlag, Berlin1994: 95-119Crossref Scopus (55) Google Scholar]. Post-exposure prophylaxis can probably only be effective before virus has entered a nerve, but as that time is unknown, patients should be treated irrespective of the time since exposure. Optimum immediate therapy is virtually 100% successful, whereas the untreated mortality from proven rabid dog bites is estimated as between 35% and 57% [7Cornwall JW. Statistics of antirabic inoculations in India.Br Med J. 1923; : 298Google Scholar,8Veeraraghavan N. Annual report of the Director 1969 and scientific report 1970. Pasteur Institute of Southern India, Coonoor1971Google Scholar]. A history of vaccination makes rabies less likely but vaccinated dogs have died of rabies. Rabies vaccines of nervous tissue origin are produced in about 13 countries. Semple vaccine is widely used in Asia, especially in India. Neurologic reactions, due to an allergic response to neural antigens, have been seen in 1:200 recipients [9Swaddiwuthipong W Prayoonwiwat N Kunasol P Choomkasien P. A high incidence of neurological complications following Semple anti-rabies vaccine.SE Asian J Trop Med Public Hlth. 1987; 18: 526-531PubMed Google Scholar,10Bahri F Letaief A Ernez M et al.Neurological complications in adults given post-exposure Semple type rabies vaccine.Presse Méd. 1996; 25: 491-493PubMed Google Scholar]. Suckling mouse brain vaccine is used mainly in South America, where neurologic complications are much less frequent, but are more severe. Safer, more potent vaccines produced in cell culture are now widely distributed, and the WHO has recommended [11WHO Consultation on intradermal application of human rabies vaccines.Wkly Epidemiol Rec. 1995; 47: 336-337Google Scholar] the original human diploid cell vaccine (HDCV) (Pasteur Mérieux), purified chick embryo cell vaccine (PCEC) (Behring) and purified vero cell vaccine (PVRV) (Pasteur Mérieux). A highly purified duck embryo vaccine (PDEV) (Berna), which has not been associated with any neurologic reactions, is also recommended. Pre-exposure immunization is often offered to expatriate residents of rabies endemic areas where dogs comprise the dominant vector. Incorporating the vaccine into the routine childhood immunizations in these areas is a possibility in the future. Pre-exposure immunization is also recommended for people at risk through handling animals, and for laboratory workers and travelers. Three doses of a cell-culture vaccine are given on days 0, 7 and 28 (or 21), either one dose intramuscularly or 0.1 mL intradermally [1World Health OrganizationExpert Committee on Rabies Eighth Report. Technical Report Series 824. WHO, Geneva1992Google Scholar,12Centers for Disease ControlRabies prevention-United States, 1991: recommendations of the Immunization Practices Advisory Committee (ACIP).MMWR. 1991; 40: RR-3Google Scholar]. The standard cell-culture post-exposure vaccine regimen requires five doses (as stated), costing >5% of the annual per capita income in many endemic areas. Two economic multiple-site intradermal post-exposure regimens have proved effective and are now approved by the WHO [3WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. 1997; (WHO/EMC/ZOO.96.6)Google Scholar,11WHO Consultation on intradermal application of human rabies vaccines.Wkly Epidemiol Rec. 1995; 47: 336-337Google Scholar], The eight-site regimen uses vaccines in ampoules containing 1 mL (HDCV, PCEC), and requires eight intradermal injections of 0.1 mL (deltoids, suprascapular, lower-quadrant abdominal wall, and thighs) on day 0, four intradermal injections of 0.1 mL (deltoids and thighs) on day 7, and a single intradermal dose of 0.1 mL on days 28 and 91 [13Warrell MJ Nicholson KG Warrell DA et al.Economical multiple site intradermal immunisation with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis.Lancet. 1985; i: 1059-1062Abstract Scopus (104) Google Scholar]. The two-site regimen with PVRV (0.5 mL per ampoule) requires 0.1-mL intradermal injections at two sites (deltoid areas) on days 0, 3 and 7, and single intradermal 0.1-mL doses on days 28 and 91 [14Chutivongse S Wilde H Supich C et al.Post-exposure prophylaxis for rabies with antiserum and intradermal vaccination.Lancet. 1990; 335: 896-898Abstract PubMed Scopus (101) Google Scholar]. Symptomatic rabid dogs usually die within a week. Isolation of virus from the saliva of apparently healthy dogs has been observed in Ethiopia [15Fekadu M. Atypical rabies in dogs in Ethiopia.Ethiopian Med J. 1972; 10: 79-86PubMed Google Scholar], Nigeria [16Aghomo HO Rupprecht CE. Further studies on rabies virus isolated from healthy dogs in Nigeria.Vet Microbiol. 1990; 22: 17-22Crossref PubMed Scopus (17) Google Scholar] and India, but so rarely that the recommendations for post-exposure prophylaxis are unaffected. Ideally, RIG should be given after the first dose of every primary post-exposure course, and is especially important following severe bites (see above) [1World Health OrganizationExpert Committee on Rabies Eighth Report. Technical Report Series 824. WHO, Geneva1992Google Scholar, 2Fathi M Sabeti A Bahmanyar M. Séroprophylaxie anti-rabique chez les sujets mordus par loups enragés en Iran.Acta Med Iran. 1970; 13: 5-9Google Scholar, 3WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. 1997; (WHO/EMC/ZOO.96.6)Google Scholar]. RIG is not needed if the patient has had a complete pre-or post-exposure course of cell-culture vaccine, or if rabies-neutralizing antibody (>0.5 IU/mL) has been demonstrated in the past [1World Health OrganizationExpert Committee on Rabies Eighth Report. Technical Report Series 824. WHO, Geneva1992Google Scholar,3WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. 1997; (WHO/EMC/ZOO.96.6)Google Scholar]. Serum sickness occurs following 1-6% of equine RIG treatments [17Wilde H Chomchey P Prakongsri S et al.Adverse effects of equine rabies immune globulin.Vaccine. 1989; 7: 10-11Crossref PubMed Scopus (28) Google Scholar], but not after human RIG treatment. Skin testing reveals type I, IgE-mediated hypersensitivity which is rarely associated with equine RIG, but not the more common reactions due to complement activation [18Malasit P Warrell DA Chantavanich P et al.Prediction, prevention, and mechanism of early (anaphylactic) anti-venom reactions in victims of snake bites.Br Med J. 1986; 292: 17-20Crossref PubMed Scopus (186) Google Scholar,19Cupo P Azevedo-Marques MM de Menezes JB Hering SE. Reacoes de hipersensibilidade imediatas apos uso intra-venoso de soros antivenenos: valor prognostico dos testes de sensibilidade intradermicos.Rev Inst Med Trop Sao Paulo. 1991; 33: 115-122Crossref PubMed Google Scholar]. A positive skin test is not a contraindication to RIG treatment [3WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. 1997; (WHO/EMC/ZOO.96.6)Google Scholar], and human RIG can be used for patients with known allergy to equine products. Adrenaline must always be available to treat anaphylaxis immediately. The mechanism by which RIG enhances immunity is by combining with vaccine antigen to form immune complexes that can be taken up by antigen-presenting cells, which stimulate T-cell activity [20Celis E Wiktor TJ Dietzschold B Koprowski H. Amplification of rabies-virus induced stimulation of human T-cell lines and clones by antigen-specific antibodies.J Virol. 1985; 56: 426-433PubMed Google Scholar]. A wide range of non-specific prodromal signs and symptoms, often including fever, marks the onset of rabies encephalitis. Two people were infected by a corneal transplant from a donor who was thought to have died of gastrointestinal infection [21Javadi MA Fayez A Mirdehghan SA Ainollahi B. Transmission of rabies by corneal graft.Cornea. 1996; 15: 431-433Crossref PubMed Scopus (55) Google Scholar]. Neurologic features soon appear. Pain or parasthesiae, especially itching, at the site of the bite wound occurs in about 40% of adults, and may be intense, resulting in excoriation. Mood changes and throat symptoms can also herald the onset of either furious or paralytic rabies [22Warrell DA. The clinical picture of rabies in man.Trans R Soc Trop Med Hyg. 1976; 70: 188-195Abstract Full Text PDF PubMed Scopus (70) Google Scholar]. The more common furious form is characterized by hydrophobia, a combination of inspiratory muscle spasm associated with terror and sometimes laryngopharyngeal spasm [23Warrell DA Davidson NMcD Pope HM et al.Pathophysiologic studies in human rabies.Am J Med. 1976; 60: 180-190Abstract Full Text PDF PubMed Scopus (65) Google Scholar]. It is precipitated by attempts to drink, or a draught of air (aerophobia), or eventually even the sound or mention of water. General arousal, wild behavior and hallucinations are interrupted by lucid intervals when the patient may have insight into his condition, a distressing characteristic not seen in other encephalitides or tetanus. The latter can also be distinguished by the persistent increase in muscle tone. Humans do not attempt to bite other people; this suggests rabies phobia which has a very short incubation period and an excellent prognosis. Other consequences of neurologic disease are peripheral nerve lesions, and hypothalamic and autonomic system defects. Paralytic rabies is less common but it is characteristic of vampire bat-transmitted infections. An ascending flaccid paralysis with sensory signs eventually results in respiratory failure. There is no reasonable chance of recovery from rabies encephalitis. Thirty years ago, two patients diagnosed by serology recovered; both had had nervous tissue vaccine post-exposure [24Hattwick MAW Weis TT Stechschulte CJ Baer GM Gregg MB. Recovery from rabies: a case report.Ann Intern Med. 1972; 76: 931-942Crossref PubMed Scopus (184) Google Scholar,25Porras C Barboza JJ Fuenzalida E et al.Recovery from rabies in man.Ann Intern Med. 1976; 85: 44-48Crossref PubMed Scopus (99) Google Scholar]. Since then, four patients have survived months or years with severe neurologic deficits [26Tillotson JR Axelrod D Lyman DO. Follow-up on rabies-New York.MMWR. 1977; 26: 183-184Google Scholar, 27Alvarez L Fajardo R Lopez E et al.Partial recovery from rabies in a nine year old boy.Pediatr Infect Dis J. 1994; 13: 1154-1155Crossref PubMed Scopus (58) Google Scholar, 28Alvarez L, Lomeli H, Baer GM, Guevara GGA, Marquez SEU, Miranda EL. Human rabies: partial recovery in two Mexican children [abstract 59.002]. In: 7th International Congress for Infectious Diseases, Hong Kong, 10-13 June.Google Scholar]. All had had cell culture rabies vaccines either pre- or post-exposure. Symptomatic intensive care is the only treatment available, as there is no evidence of benefit from steroids, RIG, α-interferon or antiviral agents [29Warrell MJ White NJ Looareesuwan S et al.Failure of interferon alfa and tribavirin in rabies encephalitis.Br Med J. 1989; 299: 830-833Crossref PubMed Scopus (50) Google Scholar]. In unvaccinated patients, rabies antibody usually appears in the blood during the second week of illness [30Anderson LJ Nicholson KG Tauxe RV Winkler WG. Human rabies in the United States, 1960 to 1979: epidemiology, diagnosis and prevention.Ann Intern Med. 1984; 100: 728-735Crossref PubMed Scopus (108) Google Scholar], and a little later in the cerebrospinal fluid (CSF). The diagnosis is made clinically in almost all cases outside the USA, but it can be confirmed during life by virus isolation early in infection from tears, saliva, CSF and brain but not from blood [31Helmick CG Tauxe RV Vernon AA. Is there a risk to contacts of patients with rabies.Rev Infect Dis. 1987; 9: 511-518Crossref PubMed Scopus (68) Google Scholar]. Rapid diagnosis from skin biopsies is achieved by immunofluorescent detection of antigen in nerve twiglets at the base of hair follicles [32Bryceson ADM Greenwood BM Warrell DA et al.Demonstration during life of rabies antigen in humans.J Infect Dis. 1975; 131: 71-74Crossref PubMed Scopus (45) Google Scholar]. This is positive in 60-100% of cases [33Blenden DC Creech W Torres-Anjel MJ. Use of immuno-fluorescence examination to detect rabies virus antigen in the skin of humans with clinical encephalitis.J Infect Dis. 1986; 154: 698-701Crossref PubMed Scopus (34) Google Scholar,34Warrell MJ Looareesuwan S Manatsathit S et al.Rapid diagnosis of rabies and post-vaccinal encephalitides.Clin Exp Immunol. 1988; 71: 229-234PubMed Google Scholar] and there have been no reports of false-positive results, which have occurred with the insensitive corneal smear test. Antigen is similarly detected in brain smears (the usual method of diagnosis in animals) and can be used postmortem on needle biopsies of brain taken via the medial canthus of the eye through the superior orbital fissure, or via the nuchal approach through the foramen magnum. A knowledge of the local epidemiology of urban and sylvatic (wildlife) rabies vectors is needed to implement control and education about prevention. Mass slaughter of stray dogs is an unacceptable and ineffective means of rabies control. Intensive dog vaccination programs in urban areas have been successful [35Larghi OP Arrosi JC Nakajata AJ Villa-Nova A. Control of urban rabies.in: Campbell JB Charlton KM Rabies. Kluwer Academic, Boston1988: 407-422Crossref Google Scholar]. Oral vaccination with either attenuated live rabies virus or a vaccinia recombinant that expresses rabies glycoprotein, distributed in suitable baits, has reduced the prevalence of fox rabies in Europe by >80% in 5 years [36Stöhr K Meslin FM. Progress and setbacks in the oral immunisation of foxes against rabies in Europe.Vet Rec. 1996; 139: 32-35Crossref PubMed Scopus (72) Google Scholar]. No such methods are yet available for dogs, but vaccinia recombinant oral vaccines are in use for raccoons, foxes and coyotes in the USA. Vampire bat rabies infection of cattle [37Flores-Crespo R Arellano-Sota C. Biology and control of the vampire bat.in: Baer GM The natural history of rabies. 2nd edn. CRC Press, Boca Raton, Florida1991: 461-476Google Scholar] causes an annual loss of millions of dollars in Latin America. Vampire bats are highly susceptible to anticoagulant at levels which are harmless to cattle. Warfarin treatment of cattle is therefore an effective method of bat population control, and hence of rabies transmission. The genus Lyssavirus (lyssa ϕ rage or frenzy) of the rhabdovirus family comprises the rabies virus (genotype 1) and six other genotypes [38Smith JS. New aspects of rabies with emphasis on epidemiology, diagnosis and prevention of the disease in the United States.Clin Microbiol Rev. 1996; 9: 166-176PubMed Google Scholar]. Five of these have caused fatal human disease. Mokola (genotype 3) and Duvenhage (genotype 4) are restricted to Africa; European bat lyssaviruses (genotypes 5 and 6) have been found in Germany, The Netherlands, Denmark, Russia, Spain, France, Poland and Switzerland; and recently a further lyssavirus of bats (genotype 7) was discovered in Australia [39Fraser GC Hooper PT Lunt RA et al.Encephalitis caused by a Lyssavirus in fruit bats in Australia.Emerg Infect Dis. 1996; 2: 327-331Crossref PubMed Scopus (156) Google Scholar]. All except the Mokola virus produced clinical signs indistinguishable from those of classical rabies. Although only eight human infections have been reported, cases may have been missed, as virologic diagnosis is unusual and the immunofluorescent antigen detection test may be negative or only weakly positive with these rabies-related strains. There is no evidence that European bat lyssaviruses (EBL) infect terrestrial animal species. An EBL-infected bat was found in an English Channel port in 1996 [40Bat rabies case confirmed.Vet Rec. 1996; 138: 630-631Google Scholar]. The protection afforded by cell-culture vaccines is probably less effective against EBL than against street rabies virus, but animal experiments have produced varying results [41King A Davies P. Bat rabies.State Vet J. 1988; 42: 140-148Google Scholar]. All the American bat rabies strains are genotype 1 lyssaviruses. In the USA [42Smith JS Orciari LA Yager PA. Sem Virol. 1995; 6: 387-400Crossref Scopus (111) Google Scholar], the most important rabies vectors, insectivorous bats, have caused 19 deaths since 1980 (86% of all indigenous human cases) (C. E. Rupprecht, personal communication). Many patients gave no history of a bat bite. Answers to the multiple-choice questions Q1: a. True; b. False; c. True; d. False; e. False Q2: a. False; b. True; c. True; d. False; e. True Q3: a. False; b. True; c. False; d. True; e. True Q4: a. True; b. True; c. False; d. True; e. True Q5: a. True; b. True; c. False; d. False; e. False Q6: a. False; b. True; c. False; d. True; e. True Q7: a. True; b. False; c. False; d. False; e. True