THE URINE AND BLOOD IN EPIDEMIC INFLUENZA

ByPeter I. Zeedick, M. D.

Epidemic influenza, unlike other acute infectious processes as diphtheria and scarlet fever, seemingly attacks the kidney in a rather mild manner. This statement refers only to the uncomplicated cases, as other bacterial or toxic agents do play a part in the nephritides occurring so often with the pneumonias or other complications following influenza. It is, however, true that in many simple epidemic cases there is evidence of a transient mild nephritis, or possibly, more correctly stated, a nephrosis. Some writers observed albuminuria in 80 per cent. of the cases, while the incidence in other reports varies from 4 to 66 per cent. It is not always stated with reference to these figures that the patients clinically were free from the common complication—pneumonia. The findings of various observers differ greatly, but they all agree that acute nephritis as a serious sequel is somewhat rare.

In the literature of the past epidemics general acknowledgment has been accorded to the presence of albumin in the urine during the acute stage of the disease. Many times this has received no further notice or comment than “febrile albuminuria.” The association of occasional hyaline and granular casts has also been mentioned. One is impressed with the fact that the older observers laid but little emphasis on the urinary findings. It also seems to be true that nephritis as a clinical entity is not prone to follow the epidemics. In general, our conclusions from the last epidemic are about the same.

The data for this paper was obtained from examination of 994 specimens of urine from 750 patients; of this number 517 specimens were examined at the Magee Hospital, where members of the S. A. T. C., all young men, were treated, and 447 specimens from the Mercy Hospital, where, in addition to the S. A. T. C., we had men, women and children. On account of the largeamount of material and work on hand, as a rule only one specimen of urine was examined from each patient, but where complications were suspected repeated daily examinations were made. We have grouped our results in tables, so that the various points may be more readily followed.

Table I shows the urinary findings of uncomplicated influenza cases admitted to the wards of the Mercy Hospital. None of these cases developed pneumonia and, after running the usual course, recovered. We would call attention to the fact that 25 per cent. showed albuminuria. The amount of albumin was never excessive, and very often was little more than a faint trace. On the other hand, we have had a few patients where a previous kidney lesion was known to be present, and naturally in these cases a heavy cloud of albumin was met with. The albuminuria was almost always a transient affair, lasting only during the acute part of the illness, and would rightly come under the class of febrile albuminuria. We regard it as being more the evidence of nephrosis than a nephritis. As a rule, the time for the appearance of albumin was after the fever had been present for at least two or three days. One rarely met with it in the short attacks of influenza where the temperature came to normal in less than 72 hours. A certain time factor appeared to be necessary in order for the nephrosis to develop. Another point of interest is the presence of red and white blood cells seen relatively frequently during the early days of the illness. One wonders if this finding is analogous to the bleeding from the nose and lung so often met with at the onset of the disease. The red blood cells were seen microscopically, and only very rarely did we encounter a smoky urine.

TABLE IURINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MERCY HOSPITAL

TABLE I

URINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MERCY HOSPITAL

TABLE IIURINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MAGEE HOSPITAL

TABLE II

URINE ANALYSIS IN CASES OF UNCOMPLICATED INFLUENZA AT THE MAGEE HOSPITAL

The results shown in Table II illustrate the urinary findings at the Magee Hospital, and, as in the previous table, include cases of influenza which did not develop pneumonia. The specimens examined were obtained from young, healthy men, between theages of 20 and 32, and showed albumin in 13 per cent. of the cases. This age factor probably accounts for the lower incidence of albuminuria for this group.

TABLE IIIURINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MERCY HOSPITAL

TABLE III

URINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MERCY HOSPITAL

Table III includes the urinary findings of patients diagnosed as influenzal pneumonia. In this table the term “Day of Disease” indicates the day on which the physical signs of pneumonia could be demonstrated, and not the day on which the patient was taken ill with influenza. The incidence of albuminuria—79 per cent.—is very high, while the presence of casts and red blood cells is low. These results are really what one would expect. As we have noticed in the late stages of uncomplicated influenza a greater tendency for urinary changes to become apparent, one would, therefore, most likely find considerable urinary disturbance in the pneumonia immediately following the epidemic disease. Pneumococcic pneumonia is prone to be accompanied byan albuminuria. So when we have both influenzal and pneumococcic etiological factors involved, it is but natural to have most of the patients showing signs of kidney disturbance. The amount of albumin present, although generally greater than in uncomplicated influenza, was not excessive. At times there was little more than a trace. We noted the relative scarcity of casts—a condition which differs greatly from our past experience in the ordinary lobar pneumococcic pneumonia. On the transient nature of this kidney involvement we have considerable positive evidence, but there is no question that the time required for the urine to return to normal is longer after pneumonia than uncomplicated influenza. We have observed but one or two cases which afterward returned to us presenting clinical signs of acute nephritis. In fact, in going over our hospital records of the winter and spring we noted that an unusually small number of acute nephritics have been admitted. This would seem to be evidence that, as has been noted in the past, the kidney is not a vulnerable organ in this epidemic disease.

TABLE IVURINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MAGEE HOSPITAL

TABLE IV

URINE ANALYSIS IN CASES OF PNEUMONIA (INFLUENZAL) AT THE MAGEE HOSPITAL

Table IV includes specimens obtained at the Magee Hospital from patients diagnosed as pneumonia. The results among these young students were very similar to those of the previous chart, where all ages were included. However, casts and red blood cells were more regularly noted.

From the four tables, we are able to note one or two common facts. In acute uncomplicated influenza albuminuria occurred 57 times in 447 specimens, or 13 per cent., at the Magee Hospital. Here we dealt entirely with the young adult. At the Mercy Hospital 88 positive results of albumin in 344 specimens, or 26 per cent., from patients of all types were recorded. The common total would be 781 specimens examined, and 141, or 17 per cent., showing albumin.

With the advent of pneumonia the incidence of albuminuria was increased. At the Magee Hospital it was seen 49 times in 70 examinations, or 70 per cent.; while at the Mercy Hospital 106 positive results were found in 133 specimens examined, a percentage of 79. The combined figures, therefore, would show 155 out of 203, or 76 per cent.

The incidence of albuminuria for the epidemic in all its phases would be, from our figures, 400 in 994 specimens, or 40 per cent.

Red blood cells were present in 5 per cent. of the influenza cases, and in 11 per cent. of the pneumonias. This was always a microscopic observation, save in the case of a slightly smoky urine. Even microscopically the red cells were not numerous. We noted them at times quite early in the disease in some of the severe cases which presented epistaxis and hematemesis. Possibly one might consider the early presence of red blood cells in the urine as a condition analogous to those just mentioned, although we never saw anything suggesting free hemorrhage from the kidney. It is probably better to regard the red cells as a manifestation of an acute nephrosis of toxic origin.

Casts were found in 35 per cent. of the cases showing albuminuria. We are inclined to feel that this observation is somewhat low, but at the same time we have noted that in uncomplicated influenza one frequently sees albumin without casts. We were also impressed with the fact that casts were not as prominent a feature in the influenzal pneumonias as they are in frank lobar pneumonia of essentially pneumococcic origin.

During the course of routine examinations several transient glycosurias were seen. Their transient character was the outstanding feature. The quantity of sugar was very moderate—our figures were never above 1 per cent.—and the daily amount of urine was always within normal limits. Acetone and diacetic acid were absent. A few observations on the blood sugar showed a rise (.2 to .25), which readily came to normal with treatment. Clinically these cases were not classed as diabetes mellitus, but rather as a nervous complication of influenza, involving in some way the carbohydrate metabolism, probably through the central nervous system. One case of special interest, which is mentioned elsewhere, was the association of glycosuria with almost total blindness from a very intense optic œdema. Sugar (1 per cent.) was present on the day of admission, while only a trace was noted on the two following days, and from then on the urine was free from sugar. How many days the sugar had been present before admission to the hospital we cannot say, but we could trace the failure of vision back to almost the day of its onset, which was three weeks previous to our first examination. The eye symptoms were the only complaints. The patient had had a moderately sharp attack of influenza a little over two weeks before the first sign of failure of vision had appeared. We may add that the vision returned slowly to normal several weeks after admission. The urine and blood sugar were normal, on a general diet, over a period of one month while in the hospital. Unfortunately, we have had no further record of this patient regarding the urine, but her vision still remains normal. Cases of this type were observed in England after the 1890 epidemic, and are referred to in Allbutt’s “System of Medicine,” vol. i, on influenza. Our other glycosuria cases did not present changes in the fundus of the eye. The glycosuria and glycæmia were transient, and we feel that they do not represent diabetes mellitus. Most of the patients of this class had long since recovered from an attack of influenza, and came to the hospital usually for treatment of various nervous conditions, which at times simulated neuritis, or otherwise one saw manifestations of general nervousness, not unlike hyperthyroidism. In all probability, we were dealing with a hyperglycæmia associated with a hyperactive thyroid gland. So, after all, the glycosuria, even though rare, is not bewildering. Symptoms and signs of toxic goitre in direct relation to theepidemic we claim to have seen, and one is justified, temporarily at least, in having the thyroid gland father our transient glycosuria.

In relation to the positive sugar findings, we have had numerous negative examples of almost equal interest. Furunculosis is a very common sequel of the epidemic. It is well known that in furunculosis there is a hyperglycæmia, but no glycosuria and no acetone or diacetic acid in the urine. All our blood sugar readings were above the normal, and at times unusually high. They varied from .2 to .41. This last unusually high amount was in a young physician with recurrent furunculosis following influenza. There was no glycosuria at any time. Elimination of carbohydrates not only brought the blood sugar to normal limits in the course of a week, but also assisted in the cure of the furunculosis, but in a longer time. In all of this group we saw no incidence of polyuria or glycosuria.

There is very little evidence, as shown in the literature, that special study on the blood during past influenzal epidemics has been made. A few references to alterations in the count of cells have been reported for the last epidemic (1890), but they are, as a rule, very brief statements. Cabot notes a normal leucocyte count in two-thirds of the cases, and a moderate increase in the rest. Several observers call attention to the leucopenia during the height of the disease, with a subsequent rise after the temperature has fallen to normal. According to Rieder and Herman (American Journal of Medical Science, 1893, cv. 696), the leucocytes were not increased in simple influenza, and only very slightly in the pneumonia following this disease. Herman also noticed a decline in the leucocytes in pneumonia as a fatal ending ensued. This finding was one of the few recorded for the 1890 epidemic. Emerson (Emerson Clinic Diagnosis, 1911, 558) found in influenza almost one-half of the cases showing more than 10,000 leucocytes, some even reaching 25,000. He further notes that early in the disease the count may be low, 3,000 to 5,000, but it usually rose sharply, to fall again when the temperature comes to normal. He lays stress on obtaining a leucocyte curve for each case in order to get a true picture of what changes occur. The past epidemic has brought out many observations on this subject.They vary somewhat, as is to be expected, but a common factor seems to be more or less basic—namely, a leucopenia or a normal count is the most significant single blood picture we have of uncomplicated influenza. Further, a leucocytosis is fairly generally, and we believe correctly, interpreted as evidence of a secondary bacterial invasion in this particular epidemic, and usually of the respiratory system. The leucopenia is as much a part of the clinical picture of influenza as it is of typhoid fever. Leucocytosis always means secondary invasion by other organisms.

During the recent epidemic the clinical laboratory department of the School of Medicine, University of Pittsburgh, has made 747 blood counts on influenza cases. In most of the cases blood counts were made as a routine, while repeated counts were done only on selected patients.

The following table indicates the leucocyte count for our series, comprising the epidemic in all of its phases. There are a few general points which appear striking that we may refer to at this time, and leave until later the discussion of the minor details. One-third of the counts, including, as they do, many cases of pneumonia, showed a leucopenia, while 70 per cent. of the total number fell under 10,000. This last group contains more pneumonias and other complications than simple influenza. But 5 per cent. of the cases counted showed more than 20,000. All of these undoubtedly had pneumonia or some other complication. Comparing this finding with our experience in the past before the epidemic with the pneumococcic lobar pneumonia, one sees at once that, as far as this type of clinical observation is concerned, the two pneumonias are totally different. The writer remembers but one case of lobar pneumonia which showed a persistent white count falling below 10,000. Certainly in this community lobar pneumonia and low leucocyte counts were unusual combinations until the present epidemic. Further, the evident depression of leucocytosis even where there was an actual increase is indicated by 95 per cent. of our counts being below 20,000. This leads us to state that the pneumococcus, although present in practically all of our pneumonias, produced in only a small percentage of the bloods we examined its characteristic increase. The toxic factor of this influenzal epidemic certainly causes a marked change in the white cells of the blood.

TABLE V

The blood picture in uncomplicated influenza is a normal one for the red cells and the hæmoglobin, but the white cells are characteristically altered. We have made many observations on the red blood cells, and from all aspects the picture appears to be normal. Similarly, there is nothing significant about the hæmoglobin estimations. Where we have slight alteration in the red count and in the hæmoglobin it is probably safer not to attribute the change to the epidemic. We have no records showing a secondary anæmia due to the initial epistaxis.

A leucopenia or a normal count is what one should see in most of the uncomplicated influenzal cases. We are almost ready to say that any estimation above normal limits means secondary bacterial invasion. The count may remain low throughout the illness, rising to the normal rapidly as the temperature falls. We do not regard a leucocytosis at the end of an epidemic case as part of the blood picture. Our experience is that with convalescence the normal count returns and remains within normal bounds. Very often hidden sinus infection is responsible for some of the post-influenzal leucocytoses. The leucopenia may vary from a slightly subnormal count to a point well below 2,000. Most of the simple epidemic cases showed some degree of leucopenia. As far as we have been able to estimate, we are led to believe that one should not lay any special stress on the grade of leucopenia as being of prognostic significance in uncomplicated influenza. Many of the mildest clinical types showed very low counts, andvice versa. There is, however, a prognostic relation to be noted with reference to a falling white count in the pneumonia, but this we shall mention again later. The onset of the leucopenia corresponds to the onset of the disease. It was present with the earliest cases we examined, and remained fairly stationary, although we have records of its fluctuating slightly one way or the other. But one must remember in this regard the personal error in blood counting, and also particularly the error of the apparatus. For careful work only those counting chambers and pipettes should be used that have a Bureau of Standards certificate. The duration of the leucopenia was fairly close to the duration of the disease.

How many cases of influenza of several days’ illness having about 12,000 leucocytes, a few sticky râles in the chest, but no signs of definite consolidation, have been observed by the clinicians? These cases recover without further change, and the diagnosis is handed in as influenza without a complication being mentioned. In collecting the blood reports from this group the 12,000 cells accordingly must be considered as having occurred in a simple influenza. We hold that this is not a case of uncomplicated epidemic disease. There is undoubted evidence, as is acknowledged by the clinician, of a bronchiolitis; and how many lungs showing a bronchiolitis at autopsy fail to have a broncho-pneumonia? True it may not be demonstrable by our physicalexamination. This is often the origin of many high counts in what apparently is considered uncomplicated influenza.

The blood picture of the pneumonia following the epidemic was more or less constant, although at the same time the features of the count may be quite different. One could roughly divide the results into three groups: (1) leucocytosis, (2) leucopenia, (3) intermediate or normal. Some pneumonias could be followed during their course through all of these classes. Before discussing the white count we can briefly dismiss the other phases of the blood examination by stating that the red blood cells and hæmoglobin presented nothing by the usual examinations which was of special significance, or in any way characteristic.

As an example of the group showing a leucocytosis let us follow a patient through an acute influenzal attack, followed by a pneumonia with a subsequent recovery. An initial leucopenia, gradually or suddenly changing into a very moderate leucocytosis (10,000–15,000), was noted at the onset of the pneumonia. During the course of the complication the number of cells in the majority of cases increased, but rarely advanced beyond 20,000. With lysis or crisis the count dropped toward normal, and by the time the lung signs had disappeared the white cells were at the usual number, or very slightly increased. The point which seemed to us to be of importance was that, even although we had a leucocytosis, it was nothing like the count that one would expect for a lobar pneumonia. Of course, there were a few high counts, but looking at the group as a whole they were relatively low. There are a number of variations to this form of blood picture which we might briefly consider. We have observed secondary rises in the leucocyte count concurrent with a new lung involvement. This type was the one so prone to develop into a condition of non-resolution, fibrosis and ultimate death, with a continuous moderately high leucocytosis to the end. Another variation which we learned to fear was the fall of leucocytes to normal or subnormal after a primary rise, when the clinical course of the case in no way indicated a crisis or lysis pending. Seemingly, the longer the primary leucocytosis had been present the more serious was the subsequent leucopenia. We regard this form of secondary leucopenia, if one may use such a term, as a prognostic sign of some value. As in lobar pneumonia, a high leucocyte count has been, as a rule, a favorable feature.

The second group, or those showing a leucopenia throughout their course, was by no means an unusual thing. This is a cardinal point—in fact, one of the most striking clinical features of the epidemic. The leucopenia here does not have the prognostic value that it seems to have in the group just referred to previously. We have observed cases go through a pneumonia with 4,000–5,000 white cells in a relatively easy manner. When, however, the leucocytes fall to 3,000 or under, one may be reasonably sure that the outcome is doubtful, even with the general condition of the patient at the time favorable. In the pneumonias of this group which died the leucocytes have always fallen to about 2,000 cells. We have a number of observations taken from one-half to four hours before death showing counts in the immediate neighborhood of 2,000, but never below this number. Where recovery has taken place the cells go forward to the normal, more or less keeping pace with the general clinical picture.

Of group three there is not much to say, except that on one hand it tends toward a leucocytosis, and on the other to a leucopenia. This group comprises a considerable number of the pneumonias. We are not in a position to say anything regarding the relative mortality of this group. The development of a leucopenia from these cases after a period of some stability in the leucocytic curve is of bad prognostic import. Not infrequently we have noticed rather wild abrupt rises to 20,000 in the leucocytes toward the late half of the disease. This curve was nearly always sustained until the end, which, as a rule, was recovery.

We do not need to consider at any length the effect on the leucocyte count of complications not of lung origin. Acute sinuses in head, otitis media and meningitis always produced a variable moderate leucocytosis. The change was not so marked in meningitis, as our cases were all preceded by a pneumonia which had independently invoked a slight leucocytic response. As a complication of the pneumonia we have noted an abrupt rise following an acute pleuritis with effusion, and similarly after the onset of an empyema. These complications seemed to be able to induce a leucocytosis with more certainty and ease than the more serious pneumonic condition. Possibly, as they occurred toward the end of the infection, the toxic factor of the epidemic influenza was more or less spent, and the secondary invader had a freer hand to act in its normal way.

Differential counts were made in 194 cases, including influenza, influenzal pneumonia and influenzal complications. We have taken the average percentage of each type of cell for the groups, which are purely numerical divisions based on the leucocytic count. No differentiation is made for the various clinical divisions of the epidemic in the following table:

The differential count in general indicates an increase in the polymorphonuclear leucocytes as the total leucocytic number increases. This is really what one would expect. There also seems to be an increase of the large mononuclear cells, with a slight diminution in the small mononuclear elements, particularly in the count below 10,000. Abnormal cells were encountered very seldom. One can hardly say that the epidemic has a characteristic differential blood picture, except, perhaps, that an increase of the large mononuclears is present in the low counts. This, however, may hold true for any leucopenia.

1. Epidemic influenza is often accompanied by a transient slight albuminuria with a few red blood cells and casts. Acute nephritis as a clinical entity does not appear to be other than a rare sequel.

2. Epidemic influenza tends to produce a leucopenia.

3. A leucocytosis in influenza, as a rule, indicates a secondary infection.

4. The pneumonia following influenza shows, as a rule, but a very moderate leucocytosis, while, on the other hand, the presence of a leucopenia is by no means infrequent.

We are greatly indebted to Miss R. Thompson, Messrs. Mock, Frost, Marshall and Scott for their assistance in this work at the Magee Hospital.

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