In infectious disease the antigen is a micro organism which may be a virus, microbe, protozoa, mycet, etc., or even a product elaborated by a microorganism. The response of an organism to the presence of an infectious antigen tends to follow the same successive stages previously outlined. If the means at the immediate disposal of the organism are qualitatively and quantitatively sufficient to neutralize the antigen, the entire process will be resolved asymptomatically. Otherwise, the first stage of the defense reaction, the primary toxic diphasic phenomenon, will be set into motion. According to the qualitative effectiveness of this response, manifestations will vary from simple subclinical changes to clinical reactions. If the second phase of the diphasic response cannot take place, a prolonged form of the first phase will result. It corresponds to shock, which is encountered only in very severe infections. The rapidly lethal condition resulting from transfusion of massively infected blood is an example.

The second phase brings chill and fever. If the second phase response is qualitatively insufficient, the prolonged form ensues, bringing fever, the usual manifestation of many infectious diseases. The fever persists as long as the nonneutralized antigen is present. In this stage of the defense reaction against a micro organism or its toxins, the symptoms, although resulting from the response of the organism, are still directly related to the presence of the antigen in sufficient quantity. The quantity necessary to induce the clinical manifestations can be reached within a short time after the penetration of the antigen into the organism. The toxic reaction thus can appear in a few hours. Consequently, there is no specific obligatory incubation time. The manifestations will disappear when the amount of antigen is decreased sufficiently. For some microbes, antibiotics have such action, resulting in a decrease in the amount of the antigen present, and consequently in the disappearance of the clinical manifestations. A similar decrease in the amount of the free antigen present can be obtained by its neutralization through specific immune sera, if available. Conseqently, such sera have curative effects in infectious diseases characterized by a primary toxic pathogenesis.

Allergic antibodies will appear after an obligatory incubation period of 6 or more days. If the antigen is still present, it may be destroyed by the new defensive antiheterogeneous responses mobilized against the resulting allergic complex. In this case, the appearance of the allergic antibodies resuits in a kind of clinical crisis which can lead to the cessation of the disease. However, if this effect does not occur, the appearance of allergic antibodies will cause an increase in symptoms or in their gravity.

In cases asymptomatic prior to the appearance of the allergic antibodies because of low direct toxicity or insufficient quantity of the antigen, the disease will become clinically apparent only with the appearance of the allergic manifestations. The clinical condition thus will have an obligatory incubation of 6 or more days, since this represents the time necessary for the coagulant antibodies to be produced. Since the manifestations in such cases are due to the allergic complex and not to the direct action of antigen, they will be nonexistent or minimal during the incubation time. Due to the allergic complex, the condition will not respond to specific immune sera able to neutralize the antigen but ineffective against the allergic complex. Specific immune sera are not curative for these infectious conditions of allergic pathogenesis. As already noted, only when administered before allergic antibodies have appeared, during their incubation period, do these sera have a marked preventive effect.

Thus the pathogenesis of an infectious disease can be toxic or allergic in nature. The two pathogenic mechanisms can be identified easily through incubation time of major clinical manifestations. An infectious disease which appears shortly after the entrance of the antigen without an obligatory incubation has to be considered, according to our concept, to be of toxic pathogenesis while one which appears after an incubation time obligatory greater than 5 or 6 days has to be considered allergic.

Applying this concept, we have separated the clinical infectious diseases into two groups, toxic and allergic, using incubation time as the criterion. We wish to note here the great similarity in the incubation time for the diseases in each group. Most of the allergic group have an obligatory incubation time ranging from 6 to 14 days, which coincides with the usual time needed for the appearance of the allergic antibodies. The incubation time is independent of the fundamental nature of the etiological agent— virus, microbe, protozoa, etc.—or of the nature of their products—exotoxins, endotoxins, etc. This indicates that the principal factor in the incubation time is the allergic pathogenic mechanism itself.

Based upon the criterion of obligatory incubation time, the following diseases with brief incubation time have been considered as having a toxic pathogenic mechanism: diphtheria, botulism, anthrax (Bac. anthracis), meningococcal infections, cholera, some streptococcal infections, dysentery (especially Shiga Kruse bac), plague, scarlet fever, pneumonia, etc. In the allergic group, with an obligatory incubation time above 6 days, we find: typhoid, typhus, tetanus, pertussis, rabies, measles, poliomyelitis, glanders, etc. (Table XII) In both groups, there are varied etiological agents. Thus, in the allergic group, for example, the antigens include a microbe with an exotoxin (tetanus) with an endotoxin (typhoid), a rickettsia (typhus), and a virus (rabies).

Table XII. Infectious Diseases. Incubation

Low

Obligatory above 6 days

Dyphtheria Anthrax

Botulism

Gaseous Gangrene

Plague

Erysipelas

Dysentery

Meningococci Inf.

Cholera

Pneumococcus Inf.

Typhoid

Tetanus

Pertussis

Glander

Tularemia

Leprosis

Typhus

Rabies

Measles

Mumps

Poliomyelitis

Smallpox

Chickenpox

Recurrent fever

The concept of toxic and allergic pathogenesis for these diseases is impressively confirmed when we consider the effects of specific immune sera upon their evolution. The specific sera demonstrate curative properties for all diseases in the first group with brief incubation time, considered in our concept because of this incubating time as toxic. Not one of the conditions of the second group, considered as allergic on the basis of their incubation time alone, can be cured by immune sera. Still more impressive is the fact that, in spite of the lack of curative effect, the same sera have a marked preventive effect upon the same allergic conditions if administered before the onset of the symptoms, that is, during the incubation period. This confirms our explanation that the therapeutic inefficiency of the sera in the second group is due to the allergic pathogenesis of the disease and not to a lack of active antibodies. Moreover, the same sera have a curative action upon infections with brief incubation periods induced experimentally in animals with the same agent. The concept has been confirmed in most of the infectious diseases and we will discuss some of these diseases briefly.

Before discussing this aspect of infectious diseases in more detail, we want to mention another occurrence which can be interpreted also through the concept of allergic conditions. It concerns a kind of recurrence of symptoms seen often around the 7th day after the beginning of the clinical condition in infectious diseases which, by themselves, have allergic pathogenesis such as typhoid, mumps, measles, pertussis, etc.

While in these cases the condition itself can be considered an allergic manifestation against the infectious agent as antigen, a 7th day exacerbation in the course of the clinical condition can be interpreted as a second allergic reaction. This time a new antigen has to be considered. This appears to occur with the first allergic manifestation, the new reaction appearing 7 days later. The complex antigen coagulant antibodies responsible for the clinical manifestations of the allergic condition could represent this secondary antigen. Besides the antiheterogeneous reaction—enzymatic and lipidic—which determine the symptoms of the condition, this complex induces the appearance of a new group of coagulant antibodies against it. Around the 7th day after the beginning of the clinical condition when these new coagulant antibodies against this secondary antigen appear, they induce the exacerbation seen.

The existence of these secondary allergic reactions toward secondary antigens, often themselves of allergic nature, explains many of the tardive manifestations seen in the course of infectious conditions.

Pneumococcic Pneumonia

This disease, which appears after a very short incubation period, has the characteristics of a primary or toxic condition, with chill marking the beginning of the clinical manifestations. Antipneumococcic immune sera, corresponding to the type or even to the subgroup of the etiologic microbe are curative when administered in time and in adequate doses. In the natural evolution of the disease, a crisis usually appears on the 8th day. This corresponds to a marked aggravation of symptoms which can be so intense as to lead to death. The term "crisis" indicates this characteristic exaggeration of the manifestations. The coincidence between appearance of the crisis around the 8th day and the moment when allergic manifestations generally occur has suggested an allergic nature for this crisis.

Usually, the course of the disease changes suddenly after the crisis. Most of the marked manifestations disappear in a short time. This allergic crisis, with an initial increase in the severity of the condition, is not seen in patients who have received specific serum which has acted to prevent the crisis as allergic reaction. In pneumonia the crisis has its beneficial effect, a fact which accords with the concept that allergic intervention provides a new opportunity to resolve the intervention of the noxious agent. As we have seen, the allergic stage represents a second, more complex method of combatting antigens. In the case of pneumococcic pneumonia, this allergic defense effort is often successful. The evolution of the disease is stopped.