PASTEUR PROPHYLACTIC TREATMENT-RECOMMENDED BY PASTEUR Some Pasteur institutes now use a modified treatment, starting with an 8-day instead of a 14-day-old cord, which is exemplified in the scheme used at the Hygienic Laboratory, Public Health Service. See table on the following page.
The tendency is to hasten the immunity by using only the intensive treatment for all cases, also to start with fresher cord, some using 4 day-old cord for the initial injection. Intensive treatment should al .
ways be given for wounds of the face, head, hand and other exposed parts of the body ; for multiple wounds ; severe wounds; or for wolf, fox, cat and skunk bites.
The scheme of Pasteur has been further modified in various ways, depending upon the method used to attenuate the virus. Thus Pasteur attenuated the virus by drying; Babes by heating; Frantzer by the use of bile; Tizzoni and Cattani attenuated the virus in gastric juice. Hog yes used fresh material in a diluted suspension ; Ferran fresh material and in increasing doses. Cumming altered the virus by dialysis. Har ris dried the fresh virus at low temperature, which is used in diluted sus pension. Other methods have been used to attenuate the virus, such as glycerin, carbolic acid, mechanical disintegration, and, lastly, antirabic serum Ferran in Barcelona, Proescher in Pittsburgh, and others in ject patients with the unaltered, fresh, fixed virus. The advantages of using the virus as fresh and strong as possible are that an active im munity is produced more quickly, and this is of.considerable importance in wounds of the face; also in wolf and cat bites, which .frequently have a short period of incubation. Further, fewer injections of the fresh virus are necessary to produce an immunity, and this shortens and sim plifies the treatment.
Harris 41 has shown that rabic material may be completely desiccated without destruction of virulence, provided the dehydration takes place at a low temperature. The lower the temperature the greater will be the amount of virulence preserved. Virus so desiccated contains per weight as much infectivity as the fresh virus. The virus thus dried is so stable that it may be standardized, permitting an accuracy of dosage hitherto impossible. The unit is the smallest amount which, when injected in tracerebrally into a full-grown rabbit, will produce paresis on the seventh day. For slight wounds Harris gives seven injections, but for severe injuries he gives two injections a day for twelve to fourteen days. Treatment at a distance from a Pasteur institute is now practical by sending a piece of cord in glycerin; or the emulsion in glycerin, in a thermos bottle; or the dry material in accordance with Harris' method. Care During the Treatment. During the treatment the patient may go about his usual business. It is not necessary to stay in bed.
The patient should, howpvprfatigue. cold, emotional stress, _ trauma, and alcohol. It has been shown that these are important pre di posing factors to the disease. It was found that customs' officers re turning to the Siberian borders after prophylactic treatment for wolf bites showed an unusual mortality, which seemed to de due to exposure to cold. The disease has been observed to be brought on after a cold bath, falling into the water, and similar depressing influences.
Complications of the Treatment. The Pasteur prophylactictreat ment Ens be complicated by (1) local reactions or (2) paralysis.
Local reactions at the site of the wound are usually trivial. Abscesses almost never occur. The local reactions consist of redness and indura tion. It is not necessarily the last injection, but rather the site of some previous injection that flares up, but soon subsides without further trouble. This occurrence increases with the progress of the treatment ; it is most frequent in the second week. As the treatment involves the introduction of a large quantity of foreign proteins into the body, it is probable that these reactions represent a phase of hypersusceptibility. See Anaphylaxis.
Paralysis. Paralysis occurs occasionally and may be fatal. This complication seems to be a mild or modified type of rabies, but there is doubt concerning its cause. There is evidence that it may be due to infection with the fixed virus or possibly to toxin—or both. Serious paralysis is a rare complication; it doubtless occurs in mild form more often than is known. It affects adults chiefly, young children almost never. Simon collected data up to and including 1911, showing the occurrences of 100 instances of paralysis among 217,774 persons treated. In this series there were 19 deaths. The incidence of paralysis seems to vary with different methods of antirabic treatment." In a case treated at the Hygienic Laboratory the paralysis came on 18 days after treatment, and was transient. H. E. Hasseltine 43 reports two cases of paralysis following antirabic treatment, with one death. The New York Pasteur Institute reports a death from "ascending paralysis," which came on four days after the treatment. W. A. Jones" reported two cases with recovery. In 1905 Remlinger, head of the Constanti nople Institute for Rabies, reported 40 cases of paralysis; Babes had 8 cases of paralysis (all mild) in 6,525 treatments; Muller found 16 cases in the literature, and had two of his own; Panpoukis, three cases; Jones, 2. Mejio •4 reported 19,800 cases treated in the Pasteur institute, Buenos Aires, of whom 24 developed paralysis, with 4 deaths. One instance was a child of six, apparently healthy a month after the Pasteur treatment. He then had a fall from a hammock; the next day his legs were para lyzed; the paralysis proved of the ascending type, fatal in two weeks.
The Immunity. Duration. The immunity appears two weeks after the treatment and lasts a varying period of depending upon the least for scuraLgears. In this respect it does not differ from other instances of acquired immunity. The Pasteur prophylactic. may be repeated in persons bitten a second time. The lower animals may also be protected. The fact that the immunity appears on the fifteenth day after the last treatment was discovered by Pasteur as a re sult of animal experimentation. The statistics of the Pasteur Institute, giving the mortality from rabies in persons following the prophylactic treatment, exclude instances in which the disease develops within fifteen days after the last prophylactic injection.
,Sassee. The nature of the immunity is not clear. It certainly is not due to an antitoxin. Immune bodies are demonstrable blood twenty days after the last injection. The activity of the virus can be neutralized by mixing it in vitro with the blood serum of an im munized animal. This neutralization is generally considered to be mi crobieidal or lytic in nature.
Degree. The degree of the immunity also varies, as is evidenced by the fact that a certain small percentage of the persons treated die of rabies.
The Results of the giving the results of the treatment are somewhat difficult to analyze, as many factors are unob tainable. Patients should be kept under observation at least a year. Exceptional cases occur one year following exposure. Cases that occur within fifteen days after the treatment are excluded from the French • statistics, for reasons that have already been stated. The figures on this basis show a mortality of less than 0.5 per cent. Better results are being obtained from year to year.
The table on the following page gives the general results at l'Institut Pasteur. Paris, since beginning the treatment.
When we compare these figures with the fact that from 6 to 10 per emit, and sometimes 16.6 per cent. of all persons bitten by rabid dogs die of rabies, the prophylactic value of the Pasteur treatment is evident. Faber found 27 deaths out of 339 persons bitten by mad dogs; nmoto, 17 per cent. ir. Nagasaki ; Babes, 15 per cent. of 995 in Hun •Sessassa Medico, Buenos Aires, XXIV, No. I, p. 10.
gary; Horsley's figures are 15 per cent. Some series of cases give a much higher mortality. Thus, of 855 persons bitten by mad dogs, col lected by Tardieu, Thamehayn, and Bouley, 399 ended in death, or 46.6 per cent. In another series of cases given by Bouley, out of 266 per sons bitten by mad dogs, 152 died of hydrophobia. But of these 120 were bitten on the face and hands, the greater danger of which has been mentioned. The mortality resulting from bites of wolves is placed by Babes at from 60 to 80 per cent.
Contraindioations. There are no known contraindications to the treatment. All f_i_ges_and sp_nditunis _ohN14:1 be treated if exposed. parently no harm is done pregnant women. I have injected patients having malaria without trouble following. The treatment may be con tinued in patients having colds, fevers, and other ailments without no ticeable harm.
When to Give the Pasteur Prophylaetio. It is sometimes difficult to decide whether the Pasteur prophylactic treatment should or should not be given. Treatment causes sufficient personal inconvenience, not to speak of the danger (however slight) of paralysis, to avoid advising it if unnecessary. In many cases it is impossible to discover whether the dog that inflicted the bite is mad or not. The rule in cases of doubtful exposure is to advise the treatment.
Persons who apply for treatment of dogbites fall into one of the five following categories with reference to the Pasteur prophylactic: (1) The dog is mad or shows suspicious symptoms: In this case, begin treatment at once.
(2) The dog is not mad : Observe it carefully for ten days, and if no symptoms develop, there is no danger of rabies in the person bitten. The treatment is therefore unnecessary. (The dog may nevertheless develop rabies after ten days and if it has been bitten by another dog should be kept in quarantine for six months.) (3) The dog is not identified: This is a common occurrence, es pecially with children. The rule in such cases is to advise the Pasteur prophylactic treatment, except in places known to be free of rabies.
(4) Exposure to saliva: Persons not infrequently apply for ad vice giving the following history: They have not been bitten, but they have been licked on the hands and face by a dog that subsequently was discovered to have the disease. Persons are sometimes similarly exposed by washing the mouth of a rabid horse. In these cases the important question is whether there were fissures or abrasions in the skin at the time. There may be little wounds in the skin not evident to the naked eye. It is possible to infect animals by rubbing the virus on the shaved skin. The rule is therefore to advise the protection which the treat ment affords in persons thus exposed.
(5) In psychoneurotic patients with a distressing phobia of rabies, it may afford comfort to give a mild course of treatment as much for its psychotherapeutic effect as for specific immunity.
The Dog. In all cases it is important to know whether the dog is mad or not. If the dog can be found and kept under observation for 10 days and no symptoms appear, the Pasteur treatment is not necessary. Animals killed early in the course of rabies may fail to show the mi croscopic evidence of the disease; thus causing an indefinite delay in diagnosis awaiting inoculation tests. Dogs that have bitten persons should not be summarily killed, but should be apprehended and turned over to the proper authority; if killed, the head should be sent to the nearest diagnostic laboratory. Should the dog develop symptoms, the question of diagnosis is all-important.
Diagnosis of Rabies in Dogs. The diagnosis of rabies in dogs may be made in four ways: (1) from the_eymptoms; (2) from the _presence ofSigd. bodies in the central nervous system; (3) from the lesions in the peripheral_g_anilia animalinocuIations.
_ 1. The symptoms may be very suggestive, but a diagnosis must al ways rest upon the pathological lesions and the inoculation tests. The course of the disease may be divided into three stages: (a) a premoni tory stage, (b) a stage of excitement, and a paralytic stage. The firs o ages may ibiTent or transient. All rabid animals invariably become paralyzed before they die. In first symptom consists solely in a change in the disposition of the animal. He is easily excited, but does not show a tendency to bite. Soon the restlessness becomes more marked, and the animal may become furious and even show signs of delirium. The dog does not fear water, as is commonly supposed, but rushes about attacking every object in his way. Dogs suffering from furious rabies have a tendency to run long distances (25 miles or more), often biting and inoculating large numbers of other animals and persons en route. Very soon paralysis sets in, commencing in the hind legs, and finally becomes general. TheramLegitlie disease is always averaging_from 4 to 5 rarely exceeding 10 days. When the stage oreicitement is brief or absent. the disease is known as dumb rabies, - 2. There is a difference of opinion concerning the significance of the Negri bodies (Neurorrhyctes hydrophobiae), which, however, are very constant in rabies_ peculiar to it. If Negri bodies are found in the treatment should be started at once. The absence of Neui bodies. however,_ does not necessarily_ mean the absence of rabies. These bodies are sometimes difficult to find, or may not be present in the parts of the central nervous system which are examined. Negri bodies are found especially in the horn of Ammon and the cerebellum; they are 1 to 23 micra in diameter; usually round or oval; strongly eosino philic; occur within and without the nerve cells; and sometimes con tain a nucleus ( ?). Owing to their resemblance to red blood cells, the finding of Negri bodies within the cells is the safest criterion.. The diagnosis may thus be established in about 90 per cent. of cases.
Negri bodies for diagnostic purposes are best demonstrated by im preiision preparations of Ammon's horn and cerebellum, stained accord ing to Van Giesen as recommended by Frothingham or stained by Bond's modification of the Mann stain. Impression preparations are made by gently pressing a microscopic slide upon the cut surface of Ammon's horn and the cerebellum and lifting with a quick movement. Care should be taken to obtain thin uniform impressions because thick impressions do not show differential staining for Negri bodies. Pieces of the Ammon's horn and the cerebellum selected for impressions should be from four to six millimeters thick. Three or four impressions to a single slide should be made from each piece of the Ammon's horn and cerebellum. Four or five pieces of each Ammon's horn and the same number from the cerebellum are sufficient. The impression preparations obtained in this way show the characteristic arrangement of the cells of the hippocampus and of the cerebellum and rarely fail to contain the Negri bodies in infected material. When the brain is badly mutilated or decomposed, impressions taken from any of the available material containing gray matter will frequently show the Negri bodies if infected.
To stain impression preparations as recommended by Frothingham the following slightly modified procedure is given : (1) Fix before the impression dries in methyl alcohol for five minutes; (2) stain at room temperature with Van Giesen, while still moist with alcohol, for eight to ten minutes; (3) wash thirty seconds with running tap water; (4) blot with filter paper. The Van Giesen stain is made as follows : Tap water 20 c. c. to 50 c. c.; saturated alcoholic fuchsin (f. Bac. Grubler) 1 drop; saturated aqueous solution methylene blue (f. Bac. Koch Grubler) one to ten drops. The amount of tap water and the amount of methylene blue required for good differentiation vary with different stock solutions of the stains. This stain changes little in three to four days.
To stain by Bond's modification of the Mann stain proceed as fol lows: (1) Fix before the impression dries in methyl alcohol five to six tninnt; (2) wash thirty seconds with running tap water; (3) stain for four to five minutes with a mixture consisting of 1.0 c. c. of 1 per mat. aqueous eosin (Eosin W. gelbl. Grubler), 0.7 c. c. to 1.0 c. c. of 1 per cent. aqueous methyl blue (Grubler) and 6.0 c. c. of distilled water; (4) wash with running tap water for thirty seconds; (5) blot with filter paper; (6) dehydrate with absolute alcohol; (7) clear with a mixture consisting of one part of xylol and two parts of aniline oil; (8) wa.-11 with ; (9) mount in balsam. The Mann stain should be freshly prepared each time it is used. In practice it is better to stain by both methods because each has its advantages and disadvantages. The Mann's stain gives definite Negri bodies but the differential staining be tween the red blood corpuscles and Negri bodies is not always clear. With the Frothingham method Negri bodies can hardly be mistaken for anything else but the stain itself may be capricious in action shows relatively fewer Negri bodies.
3. The lesions of Van Gehuchten and Nelia, described in 1900, are the most characteristic anatomical changes. These lesions are found late in the disease in the peripheral ganglia of the cerebrospinal and sympathetic systems, especially in the plexiform ganglia of the pneumo gastric nerve, and the Gasserian ganglia. The normal nerve cells of these ganglia lie in a capsule lined with a single layer of endothelial cells. In rabies these endothelial cells proliferate and the nerve cells may be partly or entirely destroyed and replaced by diverse cells as sociated with chronic inflammatory processes. In addition, lymphatic infiltration also occurs about the sheaths surrounding the individual nerve cells. Either the prolifeiative or infiltrative changes may pre dominate. In order to find these lesions, it is necessary to fix the ganglia in Zenker's fluid and to stain the sections by the eosin-methylene blue method. This method of diagnosis is available in only a small per tentage of cases.
4. The final diagnosis of rabies rests upon animal experimentation. A small quantity of an emulsion of the medulla or pons of the suspected animal is placed under the Jura mater of a rabbit or guinea-pig. The diagnosis by this method, however, requires so much time (on account of the long period ofincubation of the disease) that it is of no practical value in deciding whether or not the Pasteur prophylactic treatment should be given, but in any critical case the positive evidence furnished by animal experimentation is incontrovertible.
If the inoculated rabbit shows no symptoms in one month, and Negri bodies were not seen in the specimen, then a negative diagnosis may be given, although it is customary to observe the animal for six months.