There are few diseases the prompt recognition of which is of greater importance to the physician than variola. On the one hand, failure to recognize the disease may subject the family of the patient and the community at large to the danger of contagion, and thus even be the starting-point of a widespread epidemic; on the other hand, to pronounce a case smallpox when it is not, entails so much needless pain and anxiety that the physician guilty of so grave an error merits the severe condemnation which will certainly be visited upon him.

The recognition of a case of smallpox may be simple, difficult, or even impossible, depending on the case and on the stage of the disease. In general the disease is readily recognized when the case is typical and the eruption has reached the vesicular or pustular stage. The diagnosis is difficult in atypical and complicated cases. It is impossible with any degree of positiveness in most cases in the pre-eruption period,—the stage of invasion.

The initial symptoms of smallpox resemble the first symptoms of so many infectious fevers that it is only through a consideration of the prevalence of an epidemic and the opportunities for infection in a given case that the physician may be put on his guard. It is important in this connection to notice whether the patient has been successfully vaccinated within a recent period. The physician who during the prevalence of an epidemic finds an unvaccinated subject suffering from a febrile disease of acute onset, with severe lumbar and dorsal pains, may, in the absence of definite symptoms pointing to some other disease, suspect smallpox; but a positive diagnosis at this stage is, of course, impossible.

Prodromal Rashes.—The occurrence of the prodromal rashes, the roseola variolosa,—a more or less diffuse scarlatiniform, morbillic, or urticarial rash which may appear on the second day of the fever,—has a certain diagnostic value; but this roseola occurs in only a small percentage of the cases, and, unfortunately, sometimes appears in other acute toxÆmic conditions,—typhoid, for instance. The scarlatiniform rash may lead to a diagnosis of scarlet fever and the morbillic roseola be mistaken for measles; but these diseases would be excluded by the absence of the angina and the strawberry tongue of scarlatina in the one case and of the catarrhal symptoms of measles in the other, aside from other considerations. The appearance of the eruption on the second day of scarlatina is followed by a marked defervescence, while the scarlet rash of smallpox is not accompanied by any change in the temperature curve. The eruption in measles occurs on the fourth day of the illness, a circumstance which alone suffices to differentiate it from the morbilliform roseola of smallpox. The characteristic and pathognomonic “Koplik spots” on the buccal mucous membrane in measles are, of course, absent in smallpox. Furthermore, these prodromal eruptions of variola are of extremely evanescent character and usually disappear within eight or ten hours.

Of somewhat greater diagnostic value in this stage is the appearance of small hemorrhages, or petechiÆ, varying in size from a pin’s head to a pea, in the brachial and crural triangles of Simon. This form of prodromal eruption, however, is extremely rare, and, it may be added, is of grave prognostic significance, as it is usually the precursor of hemorrhagic smallpox.

Meningitis.—The intense headache, vertigo, delirium, and coma of meningitis, especially meningitis of the convexity without localizing symptoms, may be mistaken for severe prodromal symptoms of smallpox. As a rule, pulse and respiration are slow in meningitis, while in smallpox respiration and pulse are both markedly rapid.

Cerebro-spinal Meningitis.—In cerebro-spinal meningitis, in which an erythematous or purpuric rash appears, the difficulties of diagnosis are often such as tax the skill of the most expert clinician. It is important to remember that the rash of cerebro-spinal meningitis usually develops gradually or in successive crops, and that its distribution over the cutaneous surface is irregular, while the eruption of smallpox makes its complete appearance within the space of a few hours and is localized chiefly on the face and extremities. The stiffness at the back of the neck and the retraction of the head are symptoms that do not belong to smallpox.

SepticÆmia and PyÆmia.—Acute septicÆmic and pyÆmic conditions in which there are hemorrhagic and bullous lesions in the skin sometimes present grave difficulties in making a differential diagnosis from smallpox. In general, however, a careful elucidation of the history of the case will bring out some points that serve for differentiation.

It must be admitted, however, that the diagnosis between cryptogenetic septicÆmia and hemorrhagic smallpox is sometimes impossible intra vitam. A case of this kind may be cited which occurred in New York during the epidemic last year. A woman of thirty, not vaccinated since childhood, living in a house adjoining one from which a case of smallpox had been removed, was reported to the authorities as a possible case of smallpox. It was the sixth day of her illness, which had begun abruptly with headache, backache, vomiting, and fever. On the third day of the illness there was a profuse hemorrhage from the uterus, and thereafter metrorrhagia was almost constant. On the fourth day a scarlatiniform eruption was noticed on the legs and abdomen. The rash rapidly extended and was soon interspersed with hemorrhagic points. When seen on the evening of the sixth day the patient was semi-comatose. The skin was literally covered with a dusky scarlet rash in which were noted countless hemorrhagic macules, from a pin-point to a bean in size. The conjunctivÆ bulbi were chemotic, the tongue was swollen, and the fauces were deeply congested. The post-mortem examination made the following morning, six hours after death, revealed a septic endometritis, and streptococci were cultivated from the blood and the peritoneal serum.

Grippe.—An attack of grippe may simulate the early symptoms of smallpox very closely. The onset may be sudden, the muscular pains severe, the pyrexia decided, the general prostration as marked as in smallpox. In grippe, however, the muscular pains are, as a rule, more general than in smallpox, there is rarely profuse sweating, and symptoms referable to the respiratory tract soon develop, if indeed they are not present from the beginning.

Rheumatism.—The severe lumbar and sacral pains of smallpox have been mistaken for rheumatism, but such an error can be made only where the use of the clinical thermometer is unknown. A febrile movement in lumbago is absent or but slight, while in smallpox the pyrexia is usually pronounced.

Typhoid and Typhus.—Typhoid and typhus fevers have at times been confounded with smallpox. But errors of this kind can be made only where the history of the case is completely ignored. In typhus, it is true, the eruption, petechial and almost papular in character, may suggest hemorrhagic smallpox; but the eruption of typhus rarely appears before the fourth or fifth day of the illness and is located chiefly on the trunk, sparing the face. The rash of malignant smallpox develops usually on the third or even the second day of the illness and is not limited to the trunk.

Upon the appearance of the rash in a typical case of smallpox the febrile diseases with which it is most frequently confounded are measles and varicella. It is interesting to note that until the time of Sydenham, in the latter part of the seventeenth century, measles and smallpox were regarded as manifestations of the same disease, and that the Vienna school of dermatologists, even to this day, insists on the etiological unity of variola and varicella.

Measles.—As a matter of fact the early papular eruption of measles bears a considerable resemblance to the first stage of the eruption of smallpox. In both the eruption is noted first in the face. In smallpox, however, the papules have a firm, “shotty” feeling on palpation, while in measles they are smooth and velvety to the touch. In measles the eruption, viewed at a little distance, seems to present a distinctly corymbose or crescentic grouping, an arrangement which is absent in smallpox. The eruption of smallpox appears at the end of the third day, that of measles on the fourth day. The temperature in smallpox undergoes a rapid defervescence upon the appearance of the rash, while in measles it continues to rise after the eruption appears. The pronounced pain in the back is absent in measles, while the very marked catarrhal symptoms, coryza, conjunctivitis, etc., are lacking in smallpox. The subsequent course of the eruption will leave no room for doubt, since within twenty-four hours the papules of smallpox will have developed into characteristic vesicles.

Varicella.—In varicella the stage of invasion is usually much shorter than in smallpox, the prostration less marked, and the lumbar pains of the latter disease are absent. The eruption in varicella comes out in successive crops and runs a shorter course, so that lesions in various stages of development may be seen side by side. The temperature does not necessarily fall on the appearance of the eruption, and there may be a more or less marked rise with each fresh crop of vesicles, the temperature curve presenting thus a remittent character. The eruption itself presents marked differences in the character and the course of the individual lesions, as well as in their distribution. The clear vesicles shoot up from the surface, as it were, without warning; or there may be for a brief period only a circumscribed erythema like that which usually precedes the appearance of an urticarial wheal. The vesicles of varicella have usually a somewhat obtusely conical shape, while those of smallpox are distinctly hemispherical. The characteristic umbilication of the smallpox vesicle is wanting in varicella. It is true the varicella vesicle often shows a depression at its apex; but this false umbilication, as it is called, is due to the rupture of the vesicle and the escape of some of its fluid or to a partial drying of its watery contents, and occurs only after the vesicle has existed for some time. The vesicle of varicella appears much more superficial in its seat, and its roof is much thinner, so that it ruptures readily. Very moderate pressure with the finger suffices to break it. When ruptured in this way the vesicle usually collapses completely, contrasting in this respect with the smallpox vesicle, from which, owing to the multilocular character of the lesion, all the fluid does not escape.

In varicella the distribution of the lesions over the surface is far more erratic than in smallpox. The very decided tendency to grouping of lesions upon the face and about the wrists so characteristic of smallpox does not occur in varicella, in which the vesicles may appear even more extensively on the trunk than upon the face. In varicella the palms and the soles, except in infants, are almost never affected; while in smallpox these regions are practically never exempt. It is true that in the extraordinarily mild cases of smallpox, such as have constituted the majority of cases during the past two years throughout the West, lesions may or may not be present on the palms and soles; but in the severe and moderately severe cases, such as have characterized the recent epidemic in New York, the soles and especially the palms have practically without exception shown the lesions. The localization of smallpox lesions on the palms and soles deserves far more emphasis than is generally accorded it in the textbooks, many of which even fail to mention it all. It may be put down as a safe rule that a case showing an extensive eruption of vesicles or pustules, however suspicious in other respects, is not smallpox if the palms and soles are free.

Acne.—Among the skin diseases proper there are a few whose appearance upon hasty examination may occasion some confusion with smallpox. Acne pustulosa presents only a superficial resemblance to variola, but in cases where it is accidentally associated with an acute febrile disease, like grippe, for instance, it may give rise to some diagnostic difficulty. In these cases, however, inquiry will develop the fact that the acne lesions have been present before the inception of the febrile disease; and the presence of comedos, the limitation of the lesions to the face, chest, and back, together with the absence of any lesions on the palms and soles, will serve to exclude smallpox.

Impetigo Contagiosa.—In impetigo contagiosa there might under similar circumstances be a momentary doubt as to the nature of the illness. Impetigo lesions have no typical distribution on the surface, the mucous membranes are always exempt; the vesicle itself is extremely superficial, ruptures very readily, and is at once replaced by a crust, so that lesions in various stages, vesicles, pustules, and crusts may always be seen at the same time.

Zoster.—Zoster is, as a rule, readily distinguished by the definite grouping of the lesions in the tract supplied by one or more nerves, its asymmetrical distribution, and the more or less severe neuralgic pain that precedes or accompanies the eruption. It must be remembered, however, that in zoster, in addition to the typical grouped lesions, there are occasionally seen a few isolated vesico-pustules scattered promiscuously over the entire surface; and the difficulty of diagnosis may be increased by the occurrence of a moderate temperature movement. In these cases, to which attention was first called by Teneson, the history of the case, the presence of characteristic herpetic groups, and the evolution and course of the individual lesions will suffice to clear the diagnosis.

Drug Eruptions.—The ingestion of bromides, iodides, and quinine is sometimes followed by an eruption which may create some confusion in diagnosis. In general the drug eruptions may be distinguished by the absence of fever and of the subjective symptoms of smallpox. The bromide and the iodide acne never occur on the palms and soles, where there are no sebaceous glands, and the lesions lack the evolution and course of the variolous eruption. The erythematous and purpuric eruption of quinine may be confused with the hemorrhagic form of smallpox; but here, too, the history of the course of the illness and the absence of fever will obviate the difficulty.

Syphilis.—Of all the diseases of the skin it is the pustular syphilide which most resembles the lesions of smallpox. Dermatologists and experts in variola are agreed that the pustular syphilide may be absolutely indistinguishable from smallpox so far as the appearance and distribution of the lesions is concerned. Furthermore, the pustular syphilide is frequently accompanied by a decided febrile movement. The differential diagnosis can be made in these cases only by the closest inquiry into the history of the case and by careful observation of the course of the disease. The characteristic history of an acute illness of short duration followed by a remission on the appearance of the eruption will of course be wanting in syphilis. The syphilitic eruption is more sluggish in its evolution as well as in the course of its subsequent changes; and though there may be lesions of syphilis on the mucous membrane of the mouth, they will lack the characteristic appearance of the vesicles and pustules of smallpox in this region. The palms and soles are not apt to show any lesions in this form of syphilis; and finally some other forms of syphilitic manifestation are very often present in this polymorphic disease to give the clue to the real nature of the eruption.

In conclusion, the fact should be emphasized that there are cases of smallpox of so mild a character, with general symptoms so slight and eruption so sparse and ill-defined, as to make a positive diagnosis extremely difficult. It is a good plan to employ vaccination in such cases as a test. Within three or four days the experienced observer will be able to determine whether the vaccination is successful or not; a negative result will of course have but a moderate value, but a positive result will serve to definitely exclude the diagnosis of smallpox. In all cases of doubt, whether before or after the eruption has appeared, the physician owes it to himself not less than to the patient and the community to frankly explain to the patient or his family the difficulty in arriving at a diagnosis, and to express his suspicions that the case may be one of smallpox. It need hardly be said that such a case should be as strictly isolated as if the diagnosis of smallpox were already established.