Combinations of Diseases

COMBINATIONS OF DISEASES. A person can suffer at a given moment not only from one, but from two, three or more diseases, and in some cases there is no etiological and pathogenetic connection between them, and their coexistence in the same individual is accidental (for example, typhoid fever and hernia), while in others some connection exists. The simplest examples of non-coincidental occurrence of two diseases can be cases where one disease is a complication of another (for example, the addition of pneumonia to bronchitis, of pyelonephritis to cystitis, of pericarditis to left-sided pneumonia, of pyemia and sepsis to phlegmon, of metastases to cancer of some single organ, sometimes in more or less distant organs, etc.). In such cases, we speak of the spread of the pathological process by continuity, adjacency, and metastatic routes. The existence of extensive reflex connections makes understandable such combinations as bronchial asthma and lesions of the nasal mucosa, then the so-called 'uterismus thoracicus' (Windscheid), consisting of uterine cough, asthmatic attacks, tachycardia, etc., in certain diseases of the uterus.- In light of the doctrine of constitution, such a combination of diseases becomes more understandable, where with a certain constitutional predisposition the same individual at one age shows a tendency to one group of diseases, for example, various exanthemas, at another age to certain deviations of the autonomic nervous system and endocrine glands, metabolic disorders, etc. Conversely, there exist diseases that stand as if in antagonism to each other. Such are apparently gout and tuberculosis, progressive paralysis and cancer, cancer and erysipelas, progressive paralysis and malaria. Cancers in progressive paralytics are extremely rare: Fraenkel (1905) in Vienna found cancer only 5 times in 1,774 autopsies of paralytics. Along with the negligible percentage of cancer morbidity among paralytics, it is noteworthy that marked atherosclerosis with secondary heart changes belongs to the most typical findings in paralytics, while in cancer patients changes in the heart and blood vessels are almost entirely absent. Erysipelas has long been considered a disease capable of causing regression of cancerous neoplasms, which even served as a reason for corresponding attempts to treat cancer by artificial inoculation with erysipelas streptococcus. Patients with progressive paralysis have recently been treated with some success by inoculations of malaria. There are also indications of the moderating effect of relapsing fever on the course of typhus (Botkin, Elistratov). A special group should be distinguished, the so-called sequential diseases, which should as far as possible not be confused with complications, simple metastases, and secondary infections, although in individual cases such distinction encounters great difficulties. An example of sequential diseases can be heart valve defects after endocarditis. Secondary infections developing after the cessation of the primary disease (while there is simultaneous invasion by diverse microorganisms, we speak of mixed infection), but still standing in a certain connection with it, should also be considered as sequential diseases. To classify all cases belonging to the latter, we could together with Lubarsch as follows. 1. Late formation of metastases after complete (in the clinical sense) cure of the primary disease. Difference in forms of manifestation with identity of disease agents (example: progressive paralysis in syphilitics). 2. Microorganisms of the primary disease create in other organs preliminary conditions for the development of a completely different disease that manifests itself only after cure of the primary suffering, which in turn proceeds quite independently and independently of the introduced microorganisms, which by that time are usually dead (example: formation of gallstones after typhoid fever). 3. Poisons produced by the agents of the primary suffering provoke other pathological processes (example: chronic mental disorders after infectious diseases). 4. Transition of disease foci that were in a latent state into progressive development under the influence of the primary disease [example: progressive tuberculosis after influenza, measles or whooping cough (if the tuberculosis agent penetrated the organism only during the primary disease and gave a new disease after a more or less long interval after the disappearance of the first only due to its slow development, then this will be a late secondary infection, and not a true sequential disease)]. 5. Development of a new pathological process at the site of an incompletely cured old one and in a certain pathogenetic connection with it (example: cancer at the site of a healed stomach ulcer).

G. Sakharov. Combinations of genetic diseases can proceed along the lines: 1) pleiotropy (see), 2) linkage of traits and 3) their repulsion. By pleiotropy is meant such a phenomenon in which the same gene gives a phenotypic effect in different organs. The result of pleiotropic action of a gene can be pathological signs in one organ and quite harmless in a number of others; but one gene can give anomalies of two or more organs, which are often physiologically unrelated to each other. In the latter case, a clinical combination of two or more diseases is obtained, although in reality all of them are caused by the same genotypic defect. The impression of multiplicity of diseases is strengthened in the case when the corresponding gene varies greatly in its external manifestation (under the influence of other modifier genes or external conditions), as a result of which one disease may occur in one member of the family, another in another, their TS. in a third, etc. [see for example the pedigree of Genslen in the article by Quincke edema (fig. 1)]. Pleiotropic (in Siemens' terminology-polygenic) diseases are apparently numerous, but they are almost not studied scientifically, mainly due to doctors' ignorance of genetic issues. Examples of such diseases can apparently be gastric achylia and pernicious anemia, Basedow's disease, hysteria and tendency to tuberculosis, hemeralopia and myopia, anhidrosis, hypotrichosis and anomalies of teeth and many others. Sometimes the pleiotropic connection of two anomalies may consist in the fact that one is a direct consequence of the other (apparently visual disorders in albinism belong here). Such a connection can be conditionally called physiological. The latter may also consist in that a certain genotypic disease facilitates (or hinders) the development of a paratypic disease (for example diabetes and furunculosis). Another type of combination of diseases, depending on the linkage of genes, i.e. on their localization in one chromosome, is rarer. As a result, they are inherited together, with the exception of cases of crossing-over (see Crossing over of chromosomes), which results in the breaking of the corresponding two genes and the further separate inheritance of traits. The problem of linkage or (more generally) the problem of constructing a chromosome map, well studied in relation to Drosophila melanogaster and some other species of plants and animals, is in its initial stage of study in relation to humans. Practically, when interpreting two traits (diseases) as linked, one should keep in mind the possibility of confusion with independent Mendelian inheritance of genes, as well as with pleiotropy. Protection from confusion with pleiotropy is provided by the presence in another pedigree of the same two traits, but inherited by the type of repulsion, which occurs when the same two genes are located in homologous chromosomes. In this case, the possessor of two traits (diseases), having inherited each separately from one of his parents, transmits to each of his children only one trait (fig. 2), with the exception again of cases of crossing-over. In the literature there are individual pedigrees with two pathological

COMBINED traits that can preliminarily be interpreted as linked (provided this is confirmed by a corresponding case of repulsion). For example, this includes the case of Strebel, who observed in one family ectopia lentis et pupillae and heart defect (fig. 1); many members of this family also had myopia, but it is impossible to say whether it was caused by an independent gene or was a consequence of pleiotropy.-The coexistence of two pathological genes in an individual may not remain indifferent to each of them in the sense that each gene can be a modifier (enhancer or attenuator) of the other.