Tuberculosis of Insidious Onset and of Acute Onset: Necessity of Different Diagnostic Criteria

While tuberculosis recently has been forced down to the fifth place in the mortality records for the United States, it still holds first rank as a cause of death during the most productive period of life, from 15 to 45 years, and so remains of such importance as to demand the most careful consideration of medical men. 

 

Necessity of Early Treatment

The mortality rate is the least important problem of the disease from the racial standpoint but the most important from the standpoint of the individual. Taking its greatest toll between the ages of 15 and 45, tuberculosis furnishes social, domestic and economic problems of tremendous importance. It causes, on an average, an illness of three or four years for each patient who dies of the disease. The effect of such a chronic illness on the ambition, the efficiency, the business and professional career, the economic attainments, and the domestic and social life of the tuberculous individual, and on those who are associated with and dependent on him, even though he should secure an arrest of his disease, is sufficient to make any one stop and ponder, and wonder what he would do were he the one affected. 

The three great problems so far as the sick individual is concerned are: (1) how to produce healing of his disease; (2) how to guarantee to him physical efficiency for the future, and (3) how to reduce the time and cost of illness. So far as the race is concerned, the problem is how to prevent the disease and thus relieve society from its blighting influence on social, domestic and economic happiness. The importance of these problems is self-evident. 

We have learned much about preventing infection and are probably even more successful in decreasing the number of people who develop clinical disease after infection has taken place. We have proved that tuberculosis is curable. We have shown that to be curable with any degree of certainty it must be treated when the lesion is small. Treating it at this time not only insures to the patient the greatest chances of recovery and the highest degree of physical efficiency thereafter, but produces the result more quickly and with the least financial outlay. Our greatest problem as clinicians who are attempting to render the best service to patients suffering from clinical tuberculosis is not only to know how to treat the disease effectively but to be able to apply curative measures when a cure can be attained most readily. The real problem is how to secure prompt treatment when the disease presents itself. 

Early diagnosis and immediate adequate treatment are two essentials for the successful combating of clinical tuberculosis. Therefore, it is necessary that we learn to recognize the signs of its early appearance. 

 

Insidious Versus Acute Onset 

We, as clinicians, have been taught to expect tuberculosis to make its appearance in an insidious manner. It can come on acutely, too, and does in a much larger proportion of instances than we have been thinking; in fact, not infrequently the disease is first brought to the patient’s attention by an acute toxic syndrome accompanied by cough and expectoration. In many instances which are considered insidious the acute phase has been overlooked. Frequently it lasts only a few days and then disappears, the patient soon recovering his normal state of health and maintaining it for a period of time. In many instances, too, which seem to be acute, a previous insidious phase has been unrecognized. 

In order to make the matter of onset clear, it is necessary to understand the nature of tuberculous infection and the body’s immunity response. 

This discussion will be confined to chronic tuberculosis. Therefore, the presence will be assumed of a previous infection which has resulted in the establishment of a specific defense on the part of the host with the acquirement of a relative immunity. This specific defense has, as its most prominent expression, “allergy.” When allergy is present the host responds with an inflammatory reaction toward further infections with tubercle bacilli, or further inoculations of tuberculoprotein. This, in turn, determines the symptomatology and the course of the future disease process. A mild allergic reaction is accompanied by slight tissue reaction and few or no recognizable symptoms, while a severe allergic reaction is accompanied by marked tissue reaction and severe symptoms. 

Tuberculo-allergy is produced by the hypersensitivity of the cells which has been conferred on them by previous infection. This tuberculo-allergy being a variable, quantitatively, depends among other things on the character of preceding infections–number, size and frequency; the nature of the host’s response; the time that has elapsed between the preceding and the present infection, and the amount of tuberculoprotein which has been and now is set free to play on the hypersensitized cells. If we knew how to measure these factors we might predict with some degree of accuracy what the nature of the onset, what the symptoms, and what the after-course of any particular infection would be. But since all of these factors are variables, we can recognize only that the onset and course of different tuberculous infections must of necessity be different. Some will be insidious, others acute. 

Since tuberculosis makes its presence known by disturbances in the normal physiologic functions of the host, whenever symptoms are present, whether mild or severe, they must be taken as evidence not of a tuberculous infection but of a tuberculous disease. They show that the body of the host in combating the bacilli is doing so at the expense of the normal function of the tissues and organ. This we know from our experience in experimental tuberculosis, because no symptoms appear simply as a result of infection. The animal is just as well for a time after bacilli, even in quite large numbers, have entered his tissues for the first time as he was before, so far as we are able to judge from outward signs and from our methods of observation. Only after the immunity mechanism has been called into play does the animal react with evidence of illness. When this mechanism has once been called into play, however, the disease may manifest itself following comparatively small reinoculations of either tubercle bacilli or bacillary protein, or following larger ones; and all of its manifestation, its onset, its symptomatology and its after-course will differ accordingly. 

 

Importance of Allergy 

In order to understand tuberculosis it is essential to know the part played by allergy in the production of symptoms. The allergic inflammatory reaction may show itself during the course of tuberculosis in any and all tissues surrounding foci containing viable tubercle bacilli. This may result in anything from a simple hyperemia to an exudation of serum, cells and fibrin in the tissues and air spaces–a true pneumonic process; or, it may be, caseation with or without loss of tissue. It also shows as a response to general cell hypersensitiveness to tuberculoprotein, which is the basis of local tuberculin reactions in tissues distant from tuberculous foci, such as the skin. This specific inflammatory reaction was first noted and described by Koch and later called “allergic” by Pirquet. 

Allergy is so vital a part of every reaction that one cannot think of clinical tuberculosis except in terms of it. It is due to it that symptoms appear, that pathologic changes occur, and that variations in the course of the disease manifest themselves. Depending on its presence or absence, and on its severity, healing occurs or death takes place. 

It is well to know how the allergic inflammatory reaction produces symptoms and signs of tuberculosis; for by understanding this we shall be enabled to explain the different methods of onset of the disease. The more marked the reaction, the more severe the symptoms and the easier the infection to diagnose, as may be readily understood. The products of inflammation–bacillary, pulmonary and exudative–cause the toxic symptoms. The inflammation of the tissues injures afferent nerves and produces reflex disturbances, causes local changes which are responsible for such symptoms as hemoptysis, pleurisy and sputum and produces differences in density of the pulmonary tissues which are determined by palpation and percussion, and altered auscultatory sounds and pulmonary râles. It is the same allergic reaction, too, which causes the changes in the pulmonary parenchyma that produce the roentgen shadows and are responsible for the breaking down of foci of disease with the appearance of bacilli in the sputum. This allergic reaction, then, must be understood if one will recognize tuberculosis, for it is the cause of the phenomena on which recognition depends. 

In order to make an early diagnosis of tuberculosis it is necessary to be able to recognize the earliest manifestations of allergy that result from any given active infection. This, unfortunately, is difficult to do when the reaction is slight, whether because of a low specific sensitiveness of the body cells or because of mild stimulation on account of a small reinoculating dose of bacilli, and consequently a small quantity of tuberculoprotein. 

 

Immunity Response Of The Host To Infection 

Every infectious disease–tuberculosis, measles, typhoid, meningitis or diphtheria–calls forth an immunity response on the part of the host. This response differs according to the nature and numbers of bacteria which produce the infection, the seat of inoculation and the ability of the host to respond. For a typical disease picture to appear, one assumes that the infection must be produced by a quantity of bacteria sufficient to upset the normal physiologic equilibrium of the host while he is meeting their inroads by marshaling his immunizing forces. There is no doubt, however, that many infections take place which fall short of producing a definite disease picture and yet raise the specific resistance of the host and even create an efficient immunity to further infection by the same microorganism without the host’s being aware of their presence. This probably accounts for the many instances in which several children in a family are exposed to measles, whooping-cough or other infections, and part of them become ill while the others do not. Such children often prove resistant to the disease ever after, although exposed by contact. Sometimes, however, such infection only raises resistance relatively, and later the child develops the disease, which has a more or less typical course. The same is true in tuberculosis plus the further important fact that, when once a person is infected with moderately large doses of tubercle bacilli, viable bacilli are nearly always thereafter present in the tissues of the host to be a source of future reinoculation. 

An immunity response is associated in our minds with the idea of protection; yet, while the acute reaction lasts, it has about it many factors that are distinctly inimical to the host. The host cannot put up an adequate defense against a severe infection without some derangement of the physiologic mechanism. The toxins render many of the neurocellular mechanisms of the body unstable and may even completely disrupt the harmonious workings of many systems through the accompanying malaise, loss of vigor, elevation of temperature, quickened pulse rate, lessened appetite, impaired digestion and resultant loss of weight, leukocytosis and anemia, all of which exert, for the time being at least, a decidedly harmful influence on the patient, even though immunity may result from the reaction. If localized in some particular organ or tissue, the infection may produce such an inflammatory reaction as to disturb other organs reflexly, and locally produce harmful effects. 

Acute and chronic infections differ greatly in the competence of the immunity response which they call forth. Acute infections as a rule consist of one infection, one immunity response, and a competent and usually lasting resistance to further infection, or a failure to establish immunity, and death. Chronic infections, on the other hand, consist of repeated reinoculations and repeated immunity responses, without ever producing more than a relative immunity. In each instance the same episode on the part of the host, qualitatively, is called forth, though different episodes differ quantitatively, according to the inoculating dosage and the reacting capacity of the host at the time when the infection takes place. 

Since tuberculous infection fails to produce a competent and lasting immunity because of the inability of the host to rid himself of viable bacilli, the disease becomes chronic and during its course produces a succession of reinoculations of bacilli and bacillary protein, each of which is followed by an immunity reaction, unrecognized if very slight, manifest if more marked. We can therefore understand that the course of tuberculosis must be a succession of variable responses on the part of the host, and must have a variable course. Uniformity of onset, symptoms and course could take place only if the reinoculating dosage of bacilli were always the same in numbers and virulence and the sensitivity of the cells of the host to tuberculoprotein as well as his nonspecific resistance were always the same. 

There seem to be three variables on the part of the infecting tubercle bacilli around which differences in their reaction may be grouped: (1) numbers; (2) virulence, and (3) the tissues in which they are inoculated. 

The tissues in which they are inoculated show differences in different individuals and also differences in different organs in the same individual. 

Constitutionalists point out the difference in tissues, in their reaction and in their resistance to various diseases. Clinicians have noted the difference in reaction of different individuals who possess different endocrine dominances. Sympathicotonia, parasympathicotonia and the various combinations of these seen in practice provide a basis for different physiologic body responses. The same is true of the difference in psychic and emotional stability. When it is recalled that reaction depends in its ultimate analysis on the cells’ giving off and taking on of substances (electrolytes), it can readily be seen how those various factors which alter the cellular background of the host provide different conditions at different times for stimuli to act on; and it is only too evident that individuals with different emotional, nervous and psychic equilibria provide different degrees of stimulation for the cells under similar conditions. 

If these facts are applied to tuberculosis, one can understand that there must be differences in the manner of onset and differences in the clinical course which are presented throughout the disease; and it is further apparent how diagnostic criteria must differ in order to detect these differences. 

 

Recognition of Tuberculosis of Insidious Onset by Mild Allergic Phenomena

The onset of tuberculosis is insidious in those instances in which the numbers of bacilli engaged in the infection are too large to be rendered harmless or destroyed by the particular individual and yet not large enough to play heavily on his specific protective mechanism and cause a marked immunity response. Needless to say there are many factors connected with this mild reaction or failure of reaction which we do not understand; but we do know that any marked immunity response such as is present in all frank bacterial diseases is absent. The cause may be on the part of either the invading bacilli or the resisting host, or both. In tuberculosis one speaks only of a relative immunity or relative resistance, because absolute immunity is never attained. Such apparently mild infections, however, cannot be disregarded because they are often the antecedents of serious disease. 

It can readily be seen that the allergic reaction caused by a relatively mild infection would be slight and probably often unrecognizable. After repeated infections, however, unless the bacilli are rendered innocuous they continue to multiply and spread and produce greater quantities of tuberculoprotein in the ever-increasing number of active foci. This gains access to the circulation and stimulates and increases the immunity mechanism to an ever higher efficiency. The cells become more hypersensitive and sooner or later enough bacillary products are present to cause definite symptoms of acute illness, as they come in contact with the highly sensitized cells. 

The symptoms in these patients with insidious onset are variable. The allergic inflammatory reaction, at least early in the course, is slight. Toxins may gain access to the circulation in sufficient quantities to produce a low-grade toxemia in susceptible individuals. A slight elevation of temperature, tiredness, nerve instability and loss of usual vigor, of appetite and of a few pounds may occur. A slight hack or no cough may be noticed. It is fortunate when such patients have a pleural involvement or an hemoptysis, for then the combination of all symptoms present makes the diagnosis definite, while without these local symptoms tuberculosis might remain unsuspected. 

There is not likely to be sputum. If present, bacilli must not be expected to be found. The roentgenogram at first may show nothing that is recognized because of the mildness of the exudation. The negative information which it gives, because of the absence of a marked exudative process, may be wrong; for such a process may be brought out immediately by an allergic reaction in case of reinoculation of either bacilli or bacillary protein. This procedure should be followed in case of doubt. Physical examination is for the most part negative. In some of these cases, lagging of the side and reflex muscle tension will cause the examiner to suspect the lung as the seat of the lesion if he knows how to detect them. A marked reaction to tuberculin adds positive evidence by showing the presence of tuberculous infection, and probably by showing that the immunity mechanism is at the time or has recently been stimulated to activity. 

I have followed many such cases to find the symptoms become more apparent later. If patients with such symptoms are given instructions how to increase their vigor and save their strength, they will often improve without a definite diagnosis having been made. Even if allowed to go on in their usual way, some will get well; but others will suffer further reinoculations, larger and more frequent, until the disease manifests itself by calling out an acute immunity response with a definite toxic syndrome probably accompanied by cough and bacillus-bearing sputum. A safe rule is to keep all such patients under close observation until they are restored to normal health. 

This insidious picture may be found in the psychically and nervously stable and the physically strong, but is seen most often in those who possess unstable psychic, nerve and endocrine balance. Such individuals show symptoms to stimuli which would not be noticed by the more stable, and hence present themselves for examination, at times, when the lesion is small and the reaction slight. These are patients in whom diagnosis is most difficult, because the symptoms of physiologic instability, from which they normally suffer, are identical with those of mild tuberculous toxemia, even to slight elevation of temperature. This is the type, however, in which a correct diagnosis is most important. The reflex and local symptoms, when present in these patients, are most helpful in determining the diagnosis. It is extremely important to search for them and not allow a severe disease to develop, for when it does, because of the lowered physiologic plane on which these patients live, they do not overcome extensive lesions as readily as the more robust. 

No definite course is followed after the onset of the disease in these insidious cases. A frank disease may develop in a few weeks’ time; or there may be an arrest of the symptoms for several months, a year or several years, or definite healing may occur. This throws on the clinician a diagnostic problem that carries with it great responsibility. If the diagnosis cannot be made at once, the patient must be kept under observation until all doubt has been cleared away. 

 

Recognition of Tuberculosis of Acute Onset by Marked Allergic Phenomena

When tuberculosis manifests itself with an acute onset, for the safety of the patient it should always be recognized at once, for the resultant disease is the product of a relatively large reinoculation. Accordingly the symptoms are more severe and the resultant lesion is apt to be more extensive and more serious to the host than is the case when the reinoculation is caused by small numbers of bacilli. 

The acute onset may follow other acute infections, such as measles, influenza or pneumonia, or other stresses which lower the patient’s resistance for the time. In such instances we assume that the bacilli responsible for the infection were previously embedded in the tissues, and probably living in an apparently harmless state until, as a result of some change, either in the tissues in the way of lowered resistance or in the bacilli in the way of increased pathogenicity, conditions favorable to growth and multiplication appeared. 

In such instances, two things may happen. If the bacilli become activated and the immunity with its cellular hypersensitivity is not greatly depressed, a marked allergic reaction with frank symptoms may occur within a few hours or days. If, on the other hand, the immunity is greatly depressed, as it is in many such instances, the bacilli may become pathogenic and be implanted widely in new tissues before the host reacts with the usual syndromes of toxic, reflex and local phenomena. Again we can conceive of an individual who has developed an immunity by previous infection becoming reinfected with large quantities of bacilli from without and reacting with an acute immunity response. In the discussion of this point, however, it must be borne in mind that immunized cells offer a barrier both to the ready entrance and to the ready spread of bacilli within the body. From my study of clinical tuberculosis I assume that this barrier can usually be depended on to be sufficient to protect most adults from becoming infected from without, at least when in good health. 

The sudden appearance of symptoms, whether due to the acute termination of an insidious onset or to the sudden development of an infection produced by large numbers of bacilli, produces the same symptoms–the toxic syndrome, with the usual increased temperature, rapid pulse, malaise, nerve instability, loss of strength, lack of appetite and poor digestion, with cough, spasticity of the muscles of the shoulder girdle, lagging of the side, and sputum, quite often containing bacilli. Such an episode, so far as the toxic group of symptoms is concerned, cannot be differentiated from any other acute infection, but the cough and expectoration should direct attention to the lungs. 

The examiner should never fail to submit any expectoration accompanied by such symptoms to examination and repeated examinations, if necessary, for Koch’s bacillus. He will find bacilli present in a surprisingly large number of instances, if he uses twenty-four or forty-eight hour samples and employs one of the concentration methods in the examination. 

Sometimes this early acute onset is followed by a prolonged quiescence; at other times, by a periodic repetition of the same phenomena. The patient expresses himself as having a cold or repeated colds, but notes that unlike common colds they lower his resistance and produce a prolonged disturbance in his feeling of well being. Sometimes, on account of the marked symptoms on the part of the gastro-intestinal tract which often mark the toxic syndrome, he states that he is “bilious.” There is little difficulty in diagnosing tuberculosis with acute onset, provided one bears in mind that the immunity reaction is very often followed by a period of quiescence during which most of the toxic symptoms may disappear, either for a time or permanently. However, reflex symptoms practically always remain, and some of the local symptoms may now and then manifest themselves. Care in obtaining and analyzing the patient’s clinical symptoms will nearly always make the diagnosis clear in this type of onset, because the lesion is relatively gross. It is not necessary to rely so much on symptoms in this type as it is in that of insidious onset, for here other aids to diagnosis are usually present, but symptoms alone are usually sufficient for making the diagnosis. 

Patients with this type of onset show muscle tension and lagging of the side to best advantage. An exudative process of sufficient magnitude to be determined by the roentgen ray is usually present. During the acuteness of the attack, localized râles are usually to be found on auscultation and bacilli are quite often present in the sputum. Hemoptysis and pleurisy are frequently present. There should be no difficulty in making a diagnosis in the presence of such symptoms, if only one bears tuberculosis in mind.