STUDIES OF THE VARIATIONS IN THEANTISTREPTOLYSIN TITER OF THE BLOODSERUM FROM PATIENTS WITH HEMORRHAGICNEPHRITIS. II. OBSERVATIONS ON PATIENTSSUFFERING FROM STREPTOCOCCALINFECTIONS, RHEUMATIC FEVER AND ACUTEAND CHRONIC HEMORRHAGIC NEPHRITIS

Warfield T. Longcope

J Clin Invest. 1936;15(3):277-294. https://doi.org/10.1172/JCI100777.

Research Article

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STUDIES OF THE VARIATIONS IN THE ANTISTREPTOLYSIN TITER OF THEBLOODSERUMFROMPATIENTS WITH HEMORRHAGICNEPHRITIS. II.

OBSERVATIONSON PATIENTS SUFFERINGFROMSTREPTOCOCCALINFECTIONS, RHEUMATICFEVERANDACUTEANDCHRONIC

HEMORRHAGICNEPHRITIS

By WARFIELDT. LONGCOPE1

(From the Medical Clinic, the School of Medicine, Johns Hopkins University and Hospital,Baltimore)

(Received for publication January 15, 1936)

The observations recorded in the preceding sec-tion form a fairly satisfactory background forfurther investigations. In these studies, whichmay be regarded as controls, it was found thatthe titer of the antistreptolysin of the serumvaried within narrow limits from one normal per-son to another, 75 per cent giving titers between25 and 50 units. It was, in addition, noted thatthe antistreptolysin titer remained fairly constantin the same individual from month to month, pro-vided a hemolytic streptococcal infection did notsupervene. The antistreptolysin in the serumfrom patients affected by a variety of chronic dis-eases behaved in much the same manner as innormal persons, for only 14 out of 84 patientsgave titers above 100 units, and none gave titersof 200 units or over. The serum from a limitednumber of acute infections, caused by agentsother than hemolytic streptococci, were also ex-amined, often at frequent intervals during thecourse of the disease. Though there was a tend-ency for the antistreptolysin content to remainwithin normal limits, both during the acute stageand during convalescence, 43 of 66 cases givingtiters between 25 and 50 units, it was noted thatthe variations from person to person were a littlemore frequent than they were in the normal indi-vidual or in the chronically diseased. Titersslightly above those of the normal adult were oc-casionally encountered, 22.7 per cent of 66 casesgiving titers above 100 units and 2 patients givingtiters of 250 units. With this information inhand it was possible to consider the problem pre-sented by patients with infections caused by hemo-lytic streptococci for we may conclude, as haveothers, that the antistreptolysin titer of the serum

1 The titrations of antihemolysin were made with thetechnical assistance of Cyril Skala.

of the adult under normal conditions usually liesbetween 25 and 50 units and rarely exceeds 100units. Persons with chronic disease or acute in-fections, not known to be associated with or com-plicated by hemolytic streptococcal infections, aremore likely to show slightly higher titers than thenormal.

We have selected several forms of hemolyticstreptococcal infections for study. There are 19cases of erysipelas, 18 cases of scarlatina, 14 casesof acute tonsillitis due to B. hemolytic strepto-cocci, and 7 cases of miscellaneous infections dueto hemolytic streptococci, from two of which mi-nute hemolytic streptococci were recovered inpure culture by Dr. Long and Dr. Bliss. It wasnot possible, unfortunately, to follow any of thesepatients for long periods after recovery andsince, as was originally pointed out by Todd (1)and has been emphasized by Coburn and Pauli(2), the antistreptolysin content of the serum maynot rise until the patient has passed well intoconvalescence, our observations in many instancesare incomplete. They serve, however, a certainpurpose.

In Table I, the antistreptolysin titers of theserum from 19 instances of erysipelas are re-corded. The sera were examined at times vary-ing from the second day of the disease to the thirdmonth following recovery. It will be seen thatin the first week of the disease, the sera from 6out of 12 patients gave titers well above 100units; in the second week 6 out of 8 gave titersabove 100 units; and 5 of these gave titers of200 units or more; in the third week 5 out of 5gave titers above 100 units and four of these gavetiters of 200 units or over. After the third week3 out of 4 gave titers above 100 units and 1 ofthese gave a titer of 250 units. The table shows

277

278 ' WARFIELD T. LONGCOPE

TABLE I

Antistreptolysin titers (units per cc.) of the blood serum of 19 cases of erysipelas

Time Patient numberOf ___

determi-nation 1 2 3 4 S 6 7 8 9 10 1 1 12 13 14 15 16* 17 18 19

day12 25 50.0 125 125 125* 125 166.73 333.3 254 33.3 1255 50.0 50.067 1258 250 166.79 50.0 250

10 333.311 250 50.0121314 250 250 166.7

week250 125

3 125250 333.3

4 250mouth

2 166.7 50.050.050.050.0

3 50.0 12550.0

One month after infection of throat due to B. hemolytic streptococcus, and 1 week after acute pharyngitisdue to B. hemolytic streptococcus.

TABLE II

Antistreptolysin titers (units per cc.) of the blood serum from 1S cases of scarlatina

Time Patient numberOf__ _

determi-naIn 1 2 3 4 5 6 7 8 9 10 1 1 12 13 14 15 16t 17 18

day1I 25 50.0* *2 *100 125 ** *1253 50.0*45 256 257 50.0 50.08 25 125 50.09 25

101 1 251213 142.9 50.0 5014 100 111.1

week125 33.3

3 250 166.7 100 100 166.7 50166.7 33.3 166.7 250 166.7

4 50month

2 166.7

*Scarlatinal antitoxin.t Puerperal infection and scarlatina.

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOOD SERUM. II

that during the first few weeks of the diseasethere was usually a rapid increase in the anti-streptolysin content of the serum, but the num-

bers of observations are too small to enable one

to demonstrate that this actually occurred in eachindividual. In Case 8 the antistreptolysin titerrose from 50 units in the first week to 125 unitsin the third week. In Cases 6, 13, 18 and 19 thetiters remained unchanged throughout the course

of the disease, and in Case 13 remained constantlyat an elevated titer of 333 units for 3 weeks.

In scarlet fever, though our observations are

meager, they nevertheless show that there is thesame tendency towards an increase in antistrepto-lysin titer of the serum in the third week of thedisease (Table II). The titers are not very high,and an increase above 100 units was only noticedin 8 of the 18 cases, and above 200 units in 2cases.

TABLE III

Antistreptolysin titers (units per cc.) of the blood serutmfrom 14 cases of acute tonsillitis

Time Patient numberof de-termi-nation 1 23 4 5 6 7 8 9 10 11 12 13 14

day

2 25

3 50.0 50.0

4

5 100

6 50.0 25

7 166.7

8 125 50.0

9 p6.7

10 50.0

12 333.3

13

14

week

125 25 125

3 250

50.0 200

4 50.0 50.0 200

month

2 25 250

333

3 200

In tonsillitis these elevations were even lesscommon than they were in erysipelas and scar-

latina (Table III). There is, however, again a

tendency for the titer to rise during the latterpart of the disease or in convalescence. Five ofthe fourteen cases gave titers above 100 units inthe second or third week and three of these gave

titers of 200 or above. Case 12 demonstratesvery well the rise of the antistreptolysin titer in

the third week of the disease and the persistenceof high titers (after recovery) for three months.

In the group of miscellaneous infections due tohemolytic streptococci there are only 7 cases (Ta-ble IV). Three of these showed an increased

TABLE IV

Antistreptolysin titers (units per cc.) of the blood serafrom 7 cases of mniscellaneous infections due

to hemtolytic streptococci

Patient numberTime of

determination1 2 3 4 5 6 7

day1 33.3234 255 333.367 500

week2 1250 503 1429 50 1254 500

monthI to 2 50

555 33.3 12533.3

2pto 3 25250

3 to 4 25

antistreptolysin titer above 100 units. The num-ber of cases is so small that they are importantonly on the following account. Case 4 was a

boy, age 13, who developed a severe inf ectionperforating thei skull and involving the brain.From this pus andftrom secondary abscesses Drs.Long and Bliss cultivated minute hemolytic strep-tococci in pure culture. Minute hemolytic strep-tococci were also cultivated from the antrum inCase 6. In view of thef(act that at the presenttime there is no information as to whether minutehemolytic streptococci are capable of inciting an-tistreptolysins fpor the oxygen labile streptolysinf ormed during the growth of hemolytic strepto-cocci Group A of Lancefield, these observationsare significant. Todd (3) has recently publisheda comparative study of the streptolysins and anti-streptolysins produced by strains belonging to thedifferent Lancefield groups (3a). It was foundthat the antistreptolysin produced by a strainfrom Lancefield Group A (human) did not neu-

tralize hemolysin elaborated by strains from

279

WARFIELD T. LONGCOPE

Group B (bovine), Group C (animal), Group D(cheese), or Group E (milk). Todd states thathemolytic streptococci belonging to Lancefield'sGroups B, C, D and E are oxygen stabile and arenon-antigenic. It is therefore important to knowthat the serum from a patient bearing a severeinfection due to minute hemolytic streptococciwhich are placed by Lancefield (4) in Group F,may possess a very high antistreptolysin content.In fact, the serum from this patient (Number 4)gave the highest antistreptolysin titers that wehave so far encountered. The serum from thesecond patient (Case 6) infected witlh minutehemolytic streptococci showed no increase in anti-streptolysin above the normal on the single occa-sion upon which an examination was made.

and least frequently in acute tonsillitis and mis-cellaneous streptococcal infections.

The observations of Coburn and Pauli (2) areamong the most extensive in this connection.Single observations made 4 weeks after recoveryfrom acute hemolytic streptococcal infections ina group of 26 non-rheumatic cases showed that10 per cent following scarlatina; 16 per centfollowing mastoiditis; and 50 per cent follow-ing pharyngitis had titers below 200 units. Re-peated observations were made in 24 cases ofstreptococcal pharyngitis. The antistreptolysincurves varied a great deal in the different cases,not only in respect to the height of the titer butas to the time after infection at which the highesttiter was attained. In 55 per cent the maximum

TABLE V

Antistreptolysin titer from 58 cases of acute infections due to hemolytic streptococci

Antistreptolysin titers (units per cc.) Titers above Titers100 units 200 units +

DiagnosisTotal

25 33.3 50 100 125 142.9 166.7 250 333.3 1429 number Num- Per Num- Perof cases ber cent ber cent

Erysipelas .................... 2 4 5 2 5 1 19 13 68.4 6 31.5Scarlatina . 3 2 2 3 1 1 4 2 18 8 44.4 2 11.1Tonsillitis ..................... 2 5 2 2 1 2 14 5 35.7 3 21.4Miscellaneous ..... 2 2 1 1 1 7 3 42.8 1 14.2

Total . . ... .. . . . 9 2 13 5 9 1 6 9 3 1 58 29 50 12 20.7

These observations upon infections known tobe associated with hemolytic streptococci, whichare summarized in Table V, furnish results thatare comparable to those previously published.During the first week of the acute infection theantistreptolysin was not often increased. By thethird week of disease or of convalescence the titerincreased and in one-half of our cases was foundat this time to be above the upper normal limit of100 units. In 13 or 22.4 per cent the titer was200 units or above. Exact information as to thevariations in the antistreptolysin content of theserum in these infections, as to the period in theinfection at which the rise first occurs, and as tothe duration of an elevated titer after the infec-tion subsides is difficult to obtain, and much morestudy is required before one can completely com-prehend this problem. It appears, however, fromthese figures that antistreptolysin is most regu-larly increased in erysipelas, next in scarlatina,

level was under 200 units. Nearly all the patientsdeveloped a secondary rise some months after theprimary maximum. Moderately elevated titerssometimes continued for four to five months.From these determinations, as well as those ob-tained in healthy persons and in a variety ofchronic and acute diseases not caused by hemo-lytic streptococci, they conclude that an antistrep-tolysin titer of 200 units or above in any one per-son is a fairly clear indication of a recent infec-tion by hemolytic streptococci in that individual.

Before analyzing the results obtained from adetermination of the antistreptolysin content ofthe serum in acute nephritis, it is necessary toconsider another group of patients in which thedisease is by many thought to be associated withinfections by hemolytic streptococci. We haveselected for this purpose, 1-rheumatoid arthri-tis; 2-erythema multiforme and erythema no-dosa, both of which affections may occur during

280

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOOD SERUM. II

TABLE VI

Antistreptolysin titers of sera from cases of rheumatoid arthritis and from patients with erythema multiforme, chorea, andactive rheumatic heart disease and arthritis

Antistreptolysin titer (units per cc.) Titers above Titers aboveTotal 100 units 200 units

Diagnosis num -____ber of

12.5 16.7 25 50.0 100 111.1 125 142.9 166.7 200 250 333.3 500 1000 cases Num- Per Num- Perber cent ber cent

Rheumatoid arthritis..... 1 3 9 11 6 8 8 9 55 25 45.5 9 18.2

Erythema multiforme andnodosum 1 1 1 2 5 4 80 3 60

Chorea . . 1 2 1 2 1 8 7 87.5 4 50Rheumatic fever, acute... 1 3 3 1 8 2 5 3 9 6 4 2 47 40 85.1 24 51

Total rheumatic fever andallied conditions ........ 1 5 3 1 9 2 8 4 12 7 6 2 60 51 85 31 |51.6

the course of acute rheumatic fever; 3-chorea;and finally 4-active rheumatic fever.

It may be seen from Table VI that the anti-streptolysin content of the serum was regularlyelevated in all these conditions, except rheumatoidarthritis. In rheumatoid arthritis this was trueof the serum from less than one-half of the 55patients studied; in the active rheumatic affec-tions it was true of the sera from the majorityof the 60 cases (85 per cent). The table showsalmost precisely the reverse of the conditions as

they existed in the chronic diseases and in theacute infections that were not caused by hemo-lytic streptococci. As a matter of fact the in-crease in the antistreptolysin content of the serum

was much more striking in active rheumatic feverthan it was in such acute infections caused byhemolytic streptococci as scarlatina, erysipelas andtonsillitis; for in 31, or over 50 per cent, of theacute rheumatics the titers were 200 or above.

Table VII gives comparative figures for thehighest titers obtained during the acute phase ofa rheumatic infection (in the majority of cases

rheumatic heart disease) and in chronic inactive

heart disease (18 cases). Even though the num-

ber of cases of chronic inactive rheumatic heartdisease is small, the difference, which has pre-

viously been pointed out by Coburn and Pauli ina much larger series, is striking.

Figure 1 shows the changes taking place fromweek to week and from month to month in theantistreptolysin titer of the serum from 47 cases

of active rheumatic infection. The changes cor-

respond very well to those that have been pre-

viously described (2), and show that during thefirst few months of an exacerbation, for in onlyfive was the attack thought to be primary, thetiter was almost invariably high. With improve-ment or recovery from the attack the titer tendedto fall, at times rapidly, but at other times quiteslowly, for in two cases the titer remained above200 units for 6 months and in 6 cases above 100units for almost a year. In three cases the titerdid not rise above 100 during the course of theobservations. The highest titers were observedin the most serious cases with prolonged clinicalcourse.

These observations add nothing to what has al-

TABLE VII

Highest antistreptolysin titers from 47 cases of rheumatic fever and 18 cases of inactive rheumatic heart disease

Antistreptolysin titers (units per cc.) Titers above Titers aboveTotal 100 units 200 units

Diagnosis -num-ber of

25 50 100 111.1 125 142.9 166.7 200 250 333.3 500 1000 cases Num- Per Num- Perber cent ber cent

Acute rheumatic fever .|. 1 1 3 3 1 8 2 5 3 9 6 4 2 47 40 85.1 24 51Chronic inactive rheumatic heart

disease ........................6 5 2 3 2 1 8 5 27.7 0

281

WARFIELD T. LONGCOPE

NQAGEl"Test sitsds6 14 r

2_1A5/94 Joa3 25 2A14 46

4 16 1 /415

6 26 111r133r 39 4/a/a4a 13 4134 39 116 f~5 2y10 2 11/ 3 Ro-

1l 2R 5/2 7 4

12333/363 313 14 53/p1/2414 14 3R15 16 1,z4316 17 5/233 29'18 25 4;Is 28 1 <20 21 1/2/35I0z*

22 2/21/OS

233393 12.

24 24- I/u 32

25 14 32/,326 14 6 10/35 mAI26 /1413 -28 44

29 32 io/s/j4 Ann90 29 11/1114

32 14 1/1q3S.33 14 5/313434 14 S/si's 23 1 336 1I, /S5

38 16 11/11/92 25

39 23 1/12/3440 24 11/9 4

41 14 4/3/5 2.42 14 I/'343V42/2 o44 38 1/10/35

45 t3 /1/35

46 20 8/215

47 11 i0/2/5 A

MONTHS1 2 4 5 6 1 R q in 1121

12

FIG. 1. CURVESOF ANTISTREPTOLYSIN TITER OF THE BLOODSERUMFROM47 CASESOF ACUTERHEUMATICFEVER.

ready been published on this subject, but they are

of value since they furnish data derived frompatients with rheumatic fever in Baltimore andmay therefore be used for comparative purposes

in a study of the antistreptolysin content of theserum from cases of hemorrhagic nephritis, oc-

curring in the same region.22 It has become obvious that these control studies of

the antistreptolysin content of the serum from normalindividuals, from patients suffering from chronic diseasesand from infections other than those due to hemolyticstreptococci, as well as from infections due to hemolyticstreptococcus and from rheumatic fever are important,for Coburn and Pauli (10) have recently shown that theantistreptolysin content of the serum in healthy indi-viduals may vary to a certain extent according to thelatitude in which these individuals live. They have col-lected statistics to show that below latitude 350 the me-

dian value for healthy individuals was 71 units and thatserum from 78 per cent of the individuals showed a titerbelow 100 units. Above latitude 350 the median titer ofantistreptolysin of serum from 231 individuals was 100units and the serum from only 58 per cent of the indi-viduals showed an antistreptolysin titer of less than 100units. It will be observed that throughout our observa-tions the antistreptolysin titers are generally somewhatlower than those reported from Boston and New Yorkboth for healthy individuals and for individuals affectedby hemolytic streptococci.

As our experience with acute nephritis has in-creased we have, from time to time, over the pe-

riod in which we have been studying it, alteredour views with regard to many phases of the dis-ease and modified somewhat our conception ofthe process. It now seems probable that the dis-ease which is designated as diffuse glomerularnephritis may assume two more or less distinctforms. These two forms have been very welldifferentiated by Winkenwerder, McLeod andBaker in a survey of our cases (5).

The first is the more common. This form fol-lows in its general symptomatology and course thedescriptions usually given of the disease. Theonset follows within 5 to 21 days a more or lesssevere infection of the tonsils, respiratory tractor more rarely of the skin. It is the form thatcomplicates scarlet fever. The infection preced-ing it is in the vast majority of cases due to hemo-lytic streptococci. The onset of symptoms isusually abrupt. In the severe cases there is fe-ver, nausea, vomiting, pain in the lumbar region,suppression of urine or anuria. A peculiar formof anasarca develops rapidly. It produces a firmgelatinous swelling of the tissue, with very little

282

VEARSI 1

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOODSERUM. II

pitting. There is a precipitous rise in blood pres-sure, occasionally acute dilatation of the heart andsometimes dyspnea. Costovertebral tenderness isfrequent. There is albuminuria, sometimes ofonly moderate degree, but the urine contains nu-merous red blood cells, casts of many varietiesand frequently many leukocytes. Rarely hemor-rhages and exudates are seen in the retina. Inthe severest cases, there is reduction of phthaleinexcretion, elevation of nonprotein nitrogen of theblood and a low urea or xylose clearance.

Milder forms are quite common. In thesethere may be no fever, only slight facial edema,only transient hypertension, and no alteration inthe renal function except for the inability to con-centrate the urine normally. The hematuria, al-buminuria and cylindruria are distinctive.

The particular features that distinguish thisvariety from the second form are the precedingacute infection always accompanied by a more orless severe constitutional reaction, the sudden on-set, the time of which is often unmistakable, andthe rapidity with which many cases improve. Inrare instances the patient dies either from theoriginal infection, an associated infection such aspneumonia, or in acute uremia. Much more of-ten the improvement from the acute stage even insevere cases is comparatively rapid. The patientmay later pass through various phases of the dis-ease and experience exacerbations with recurringstreptococcal infections, or in unfavorable casespass into a nephrotic stage much like that ob-served in the second form. Eventually, however,recovery or complete quiescence takes place in afair majority of patients (85 per cent of 61 casesof this type). Once complete recovery has beenestablished, recurrences and exacerbations havenot been observed, even though the patient mightsuffer at one time or another from an acute in-fection due to hemolytic streptococci.

The second form (designated Type B) is dis-tinctly less common. Two distinguishing fea-tures are; first, that the disease is not usually pre-ceded by any infection of which the patient isaware, and secondly, that the onset is so insidiousthat the exact time of its appearance can not oftenbe accurately ascertained. In the majority ofinstances the patient first notices swelling of thefeet, which gradually involves the entire body.

In other instances albumin is found accidentallyin the urine, and edema appears later. Usually,there are no other initial symptoms. The bloodpressure is normal or only moderately elevated,the retinae show edema, but no exudates or hem-orrhages. Albuminuria is marked, there is hema-turia of varying degree and cylindruria. Therenal function, otherwise, is rarely affected.Careful examination usually reveals some chronicor indolent infection. This usually affects theaccessory facial sinuses, the tonsils or thelower respiratory tract. The infection isoften, but not always associated with hemo-lytic streptococci, sometimes of the alphatype. At times only the minute form ofhemolytic streptococci, described by Long andBliss (5a), has been obtained in culture. Thecourse is often punctuated by acute exacerba-tions with increased blood pressure, gross hema-turia and increase in albuminuria. Though thepersistent dropsy is one of the characteristics ofthis type of the disease, edema may almost dis-appear, spontaneously, following such an acuteexacerbation. Edema usually persists for monthsand may be present off and on for years. Thepatient may die in the subacute nephrotic stage afew months or a year or two after the onset, ormay progress to a quiescent stage, with little orno edema, and only moderate hypertension, butwith marked albuminuria and constant micro-scopic hematuria that varies in degree from timeto time. Under these circumstances, the diseaseoften terminates with hypertension, and the pa-tient dies in uremia with some edema. In 25cases of this type there were no complete recov-eries, for the disease was fatal or resulted in aslowly progressive chronic and incurable nephritisin all.

It has seemed desirable, therefore, to considerthe antibody response to streptolysin as it was ob-served in three separate groups of cases of nephri-tis. Types A and B include all the instances ofhemorrhagic nephritis of which there were 97.Type C does not include any instances of hemor-rhagic nephritis.

There were 78 cases of acute active hemor-rhagic nephritis belonging to the form first de-scribed (Type A). Thirty-six of these patientshave recovered, 17 of them having been followed

283

WARFIELD T. LONGCOPE

TABLE VIII

Highest antistreptolysin titers of serum from 57 cases of hmrrhagic nephritis (Type A), 19 cases of hemorrhagic nephritis(Type B) and 18 cases in the miscellneous group (Type C)

Antistreptolysin titers (units per cc.) Titers above Titers aboveTotal 100 units 200 units

Diagnosis herof-10 12.5 14.2 16.7 20 25 33.3 50 100 111.1 125 142.9 166.7 200 250 333.3 500 cases Num- Per Num- Per

her cent herI cent

Acute hemorrhagic nephritis (Type A)

Acute stage ....... 1 3141 3 1 7 3 7 3 2 36 26 72.2 15 41.6Quiescent and

chronic.... 1 5 2 9 5 4 4 1 31 9 29 1 3.2

from nephritis.. . 3 14 2 8 3 1 1 1 1 1 1 36 6 16.6 3 8.3

Hemorrhagic nephritis, latent onset (Type B)

Latent onset, ac-tivestage .... 2 1 1 1 7 1 2 3 1 19 6 32.1 0

Miscellaneous group (Type C)

Misemllaneous,highest titers...1 i 1 2 2 1 7 3 18 3 16.6 0

Millaneous,lowest titers. .4 3 1 2 14 1 2 18 2 11.1 0

from the acute stage of the disease. The strepto-lysin content of the serum from the remaining 19cases was determined only after recovery. Therewere 40 patients who are now in a completelyquiescent stage of the disease, or in whomthe dis-ease has progressed to a chronic stage or has beenfatal. Four of the deaths occurred during theacute stage of the disease, 4 during the chronicstage. Nineteen of these 40 patients have beenexamined repeatedly from the acute stage of thedisease throughout their illness. Two patients, inaddition to those already cited, have been exam-ined and are still in the acute stage of the disease.

Table VIII gives a resume of the principaldata bearing directly on the problem under in-vestigation in all patients grouped in Type A.The infections preceding the onset of the acutenephritis in the 78 patients designated as Type Awere: scarlatina in 6 cases, erysipelas in 2 cases,and a severe tonsillitis, sinusitis, bronchopneu-monia or infection of the skin in 59 cases. Inthree cases the acute nephritis, which was quitesevere in one instance, developed during an acuteattack of rheumatic fever with rheumatic heartdisease. A severe acute infection, therefore, wasknown to precede immediately the onset of the

symptoms of acute nephritis in 70 of the 78 cases.Excluding the instances of scarlatina, erysipelasand rheumatic fever, cultures were obtained eitherfrom the infected tissue or from the seat of theinfection at different periods during the courseof the nephritis in 66 of the remaining 67 cases.Either hemolytic streptococci of beta type, or theminute type, or of both types were obtained inculture from 58 of these 66 cases. It is impor-tant to note, therefore, that more or less severeacute infections due to hemolytic streptococci wereknown to initiate the symptoms of acute nephritisin the vast majority of the cases grouped asType A.

There were 19 cases of hemorrhagic nephritiswith latent onset, described as the second type" B." Four of these have died, the others havebeen examined repeatedly during the active pro-gressive stage of the disease.

In contrast to the patients belonging to theform of acute nephritis termed Type A, the pa-tients in Type B rarely gave a history of an acuteinfection, and when upon examination an infec-tion was discovered, it was found usually to bechronic in nature. Chronic infections, often ofthe facial sinuses, were actually detected in 11 of

284

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOOD SERUM. II

the 19 cases. In several instances these infec-tions were unsuspected by the patient. Thesechronic infections were usually associated withhemolytic streptococci, for in 15 of the 19 caseshemolytic streptococci of one or another type werecultured in significant numbers and often on sev-eral occasions from the nasopharynx, tonsils, orfrom the discharge from the sinuses.

In Type C have been placed a miscellaneouscollection of cases of renal disease, including py-elonephritis, bichloride of mercury nephrosis,amyloid nephrosis, and indeterminate forms ofBright's disease seen in the chronic edematousstage. There were 18 of these cases, many ofwhich were observed for several months.

Table VIII presents the highest antistreptolysintiters of the serum from the nephritic patients be-longing to all three types. It will be seen imme-diately that the greatest number of high titers wasobtained with the serum from patients studiedduring the acute phase of the disease (Type A).All patients in Type A examined during this stageof hemorrhagic nephritis, including those thatdied during the acute phase, those that progressedto a chronic course, and those that recovered, havebeen placed in this section. There were 36 pa-tients, 26 of whom, or 72.2 per cent, gave titersabove 100 units, and 15 of whom, or 41.6 percent, gave titers above 200 units.3 Of the totalnumber, 17 recovered, 13 progressed either to aquiescent or chronic stage, 4 died during the acuteattack, and 2 are at present still in the acute phaseof hemorrhagic nephritis.

In the chronic or quiescent stage of the disease(Type A) high titers were occasionally met within some patients, but they were much less com-mon than during the acute stage. Only 9 of the31 cases gave titers above 100 units, and only 1patient gave a titer above 200 units. In thehealed stage of the disease (Type A) after com-plete recovery, high titers were still less common,for only 6 of the 36 cases gave titers above 100units. Five of the six cases that gave titers above100 units were examined within one year afterthe onset of the nephritis.

3 Since the compilation of this data, 8 additional casesof hemorrhagic nephritis Type A, in the acute stage, havebeen examined. In 4, the antistreptolysin titers of theserum were between 111 and 250 units; in 2, it was 1250units; in 1, 1666 units; and in 1, 2,000 units.

The situation in this group of patients (TypeA) is somewhat analogous to that noticed in rheu-matic fever. Though the increase in antistrepto-lysin in the serum from patients with acute hem-orrhagic nephritis is not quite so common anddoes not often reach quite so high a titer as it doesin acute rheumatic fever, the results approxi-mate more nearly rheumatic fever than any ofthe outspoken instances of infections due to hemo-lytic streptococci that we have studied. In addi-tion, the same relationship holds between the twodiseases in the acute and healed stages.

Whenthe antistreptolysin response in the activestage of the disease in patients belonging to TypeB, with latent onset, is compared with that in theacute hemorrhagic form, Type A, the difference isvery striking. The determinations were fre-quently made at approximately the same time af-ter onset of the disease in these two groups. Inthe patients with latent onset the highest titersrarely exceeded 100 units and in no case werethey above 200 units.

Finally the 18 patients in the miscellaneousgroup of nephropathies, termed for convenienceType C, present interesting features. Repeateddeterminations of the antistreptolysin titers weremade on many of these patients over severalmonths, and consequently it scarcely seems pos-sible that the unusual results are due to chancefindings. Both the highest and the lowest titersare recorded. The characteristic feature is thevery low titer of the serum obtained in severalpatients. This is frequently comparable to thelow titers obtained by Lippard and Johnson (6)in infants under 18 months of age. All of thesepatients with very low titers were edematous. Insome patients the antistreptolysin persisted at ab-normally low titers for months. The serum fromone patient gave titers that varied between 5.5units and 10 units in 14 tests over a period offour months. A second patient gave titers on 9occasions varying from 8 to 10 units over a pe-riod of 6 months, and a third patient gave titerson 7 occasions varying from 10 to 12.5 units overa period of 6 months. No explanation can beoffered for these abnormally low titers of anti-streptolysin.

Since it was desirable to obtain informationconcerning any possible relationship that mightobtain between the variations in antistreptolysin

285

WARFIELD T. LONGCOPE

content of the serum and the progress of hemor-rhagic nephritis, the antistreptolysin curves havebeen charted week by week and month by monthin 17 of the 36 cases who recovered (Figure 2),and in 19 of the 40 patients who are now in thequiescent stage, who have progressed to a chronicstate or who have died (Figure 4).

rhagic nephritis as they were in acute rheumaticfever, and that a larger proportion did not riseabove the limits of normal at any time during thecourse of the disease.

No constant relationship could be found be-tween the severity of the attack of acute nephritisand the height of the antistreptolysin titer, for

-t 8 1IO1121 1 1

YEARS2 1 11-T 1 181

FIG. 2. ANTISTREPTOLYSIN CONTENTOF SERUMFROM36 PATIENTS WITH HEMORRHAGICNEPHRITIS TYPE AWHOHAVE RECOVERED.

The curves for the patients who have recoveredhave been charted in Figure 2. In general thetrend of the curves simulated that obtained inacute rheumatic fever, inasmuch as the antistrep-tolvsin titers in the majority of the patients were

high in the first weeks or even months of thedisease. As convalescence was established andas recovery took place, the curves tended in sev-

eral cases to decline to the normal levels. One tofive years after complete recovery was established,the titers from all but two of 29 cases were

within normal limits, and in 24 cases lay between16.7 and 50 units. Though the general appear-

ance of the curves resembles that in acute rheu-matic fever, it was found, as the chart shows, thatthe original titers were not so high in acute hemor-

some patients, suffering from much the same

form of infection preceding the attack of nephri-tis, showed totally dissimilar curves, with hightiters in one and persistently low titers in another(Figure 2, Number 4, and Figure 4, Number 19).The rapidity with which the titers fell to low lev-els did not seem to be regularly allied to the formof infection caused by hemolytic streptococci, to

the severity of the nephritis, or to the rapiditywith which the patients recovered from the ne-

phritis (Figure 3). After comparatively mild in-fections, followed by attacks of nephritis of onlymoderate severity with rapid recovery, the anti-streptolysin titer remained high in some patientsfor months, whereas in others, having severe in-

fections followed by alarmingly severe attacks of

MONTHS31 4

286

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOOD SERUM. II

nephritis, the titers fell rapidly with recovery(Figure 2, Number 5; Figure 3, Number 11).Whenever the titer was high during the acutephase of nephritis, it remained elevated in mostcases beyond the time at which all evidences ofnephritis had entirely disappeared (Figure 2,Number 5).

Another interesting irregularity was the suddensecondary rises in titers after the patient had re-covered and after the antistreptolysin content ofthe seruml had dropped to a normal figure. This

streptococci in the pharynx of these patientsmight account for such irregularities. Examnina-tion of the bacteriological flora of the throat fromthe patients who have recovered have been madein many instances by Dr. Long, within a fewmonths or weeks of the timie that the titers ofthe serumn were determined. Seventeen of thecases have given at least one positive culture; 16of the cases did not at any time show hemolyticstreptococci, and in three cases cultures were notobtained. Since 12 of the cases witlh low titers

MONTHS YEARS

tni ts i 2 3 4 5 6 1 8 9 10 11 12 1

333

\ TONSILLECTOMYW=WELL

FIG. 3. ANTISTREPTOLYSIN CONTENTOF SERUMFRONI 3 CASES OF ACUTE HEMIOR-RHAGIC NEPHRITIS TYPE A THAT HAV-E RECOVERED.

occurred in seven patients. In one (Figure 2,Numiber 6) the secondary rise could be explainedby the fact that the patient contracted an attackof impetigo due to hemolytic streptococci. Thisinfection was not accompanied or followed bysigns of exacerbation of hemiiorrhagic nephritis.One of the other four patients had rheumiiaticfever, but the rise of titer in the remaining 5cases was not connected, as far as could be dis-covered, with any infection due to hemolyticstreptococci (Figure 3, Number 20). In onepatient (Figure 2, Number 15) the secondary risewas of comparatively short duration. It is, how-ever, possible that the mere presence of hemolytic

gave, on at least one occasion, a positive culturefor B. hemolytic streptococci, it hardly seemls pos-sible that the temporary carrier state could ac-count for high antistreptolysin titers. All of thepatients with high titers after recovery showedlhemolytic streptococci in the throat culture onl oneor more occasions, but in three of the five cases inwhich an adequate explanation was not found,the examinations and titers were made within 4to 7 months of the acute attack of nephritis. Inone instance, Figure 3, Number 20, the high titerwas obtained 2 years after the attack.

The antistreptolysin curves for 19 patients inwhom the acute hemorrhagic nephritis (Type A)

287

WARFIELD T. LONGCOPE

progressed to a quiescent stage, became chronic orcaused death, are charted in Figure 4. They pre-sent a somewhat different appearance from thosein Figure 2, for the curves usually remain per-sistently higher or are broken by sudden eleva-

MONTHS227

patients the titer was high during the first fewweeks of the disease (during first month in 21and during first two months in 31 of 35 cases),though in a few the titer never rose above thenormal figure. There was a tendency for the

YEARS

JmV6--j \ j TONSILkECTOMY VT¢-D *-ADENOIDECTOMYla D=DEAD

e.SINGLE READINr1.

FIG. 4. ANTISTREPTOLYSIN CONTENTOF SERUMFROM19 PATIENTS WITH HEMORRHAGICNEPHRITIs TYPE A WHOHAVE PROGRESSEDTO LATENT OR CHRONICSTAGE OR WHOHAVE DIED.

tions which are coincident with remitting acuteinfections accompanied by exacerbations of thenephritis. This is especially noticeable in Cases19, 27 and 31 (Figure 5). It is also to be ob-served that high titers persist in some cases formany months or years (Figure 5, Number 27)and were found in one case (Figure 4, Number36) from 4 to 7 years after the primary attack ofnephritis. In a few cases, notably Numbers 17and 26 (Figure 4), the titers never rose abovenormal. One of these patients has been followedfor 3 years.

From a study of the curves of the antistrepto-lysin titers in these 36 patients, 17 of whom re-covered (Figure 2), 19 of whom are now inquiescent stage, have progressed to a chronic stageor are dead (Figure 4), it may be said that novery constant relationship was found to exist be-tween the form of the disease and the curve ofthe antistreptolysin titer. In the miajority of all

antistreptolysin titer to fall as the patient recov-ered, but high titers were obtained weeks ormonths after complete recovery had been estab-lished, and occasionally there was a secondaryrise, months or even a year or two following com-plete recovery and after the titer had previouslyreached normal.

While the disease was still quiescent or whenit progressed to a chronic stage, the antistrepto-lvsin titer remained at a high level in a fair pro-portion of instances, and in some persisted atthese levels for years.

It is important to bear in mind that in the vastmajority of these patients comparatively severeinfections by hemolytic streptococci preceded theonset of the nephritis by an interval of a few daysto a few weeks, and that in many of the chroniccases evidence of infection persisted throughoutthe course of the disease.

The 19 patients of Type B with latent onset

288

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOOD SERUM. II

MONTHSuLnits i 'A 3 4 5 6 7'

TYEARS

8 9 10 11 12 1 2kI I I

T-ACUTE TONSILLITIS (3H.St.SEVERE EXACER:BATIONOF NEPHR1TIS.

ANTISTREPTOLYSIN CONTENTOF SERUMFROM3 CASES OF ACUTE HEMOR-RHAGIC NEPHRITIS TYPE A IN QUIESCENT OR CHRONIC STAGE.

MONTHSNQ0ME lsTest Inuts 2

1 26 I1/5/3 42 38 1/3/sR3 23 1o/21,A24 22 9/1/34 3

5 4Y 1/3Y36 24 10/22a2 2.7 49 it#08 21 Il/8/33 200

9 20 2/tS510 42 M/86P3 HE11 21 12A13/331233 14213 15 a3)M/3314 21 5/2/33 1m15 11 1/2oAs1618 4//35

18 24 1o/24,s mAis 215 /7 t 4,__ +

YEARSc-MOqRA-V 1 - 2 2-'

I II.q A-4 A-S 5-6 6-8

t1ACUTE TONSILLITIS HAEM. STREPT.TONSILLECTOMY

S-DENTAL EXTRACTION-RECRUDESCENCEO-SIMLE READINGD DEAD / |13

5-

FIG. 6. ANTISTREPTOLYSIN CONTENTOF SERUMFROM 19 CASES OF HEMORRHAGICNEPHRITIS TYPE B.

289

2FFIG. 5.

42D-lq

WARFIELD T. LONGCOPE

present an interesting problem. Antistreptolysintiters were determined in at least 8 of them duringthe first three months of the disease, or as nearthis time as could be determined from the his-tories (Figure 6). The characteristic of thesecases (Type B) was the persistently low level ofthe antistreptolysin titer. In only 5 out of the 19cases did the titer rise at any time above the nor-mal level, and in 2 this occurred just before death.It will also be noted that these low levels persistedfor months and years. Two cases are of particu-lar interest, Numbers 9 and 6 (Figure 6). Pa-tient Number 9 experienced, during the fourthmonth of her disease, a severe acute attack oftonsillitis due to B. hemolytic streptococci. Thiswas accompanied by gross hematuria. Imme-diately after this acute attack, the antistrepto-lysin titer rose from 12.5 units to 16.7 units,and during the next two weeks rose abruptlyto 100 units. During the following two monthsthe titer varied from 50 units to 33.3 units,but at no time, even after the acute infection,did the titer rise above normal. Patient Num-ber 6 had shown variations in titer between10 and 25 units for about 2 years when suddenlyafter an infection about a tooth, which later wasextracted, the titer rose from 50 to 125 units,where it has remained for 8 months.

Another interesting feature is the very lowtiter which at times these patients may show. Ti-ters between 7 and 10 units were obtained on oneor several occasions with the blood serum from 4of these patients (4, 5, 6, 9).

The explanation for the persistently low titersin the patients of this type is not clear. Prac-tically all of them have had or now have more orless marked edema though, in several, during thelatter stages of the disease this has been confinedto slight pitting over the shins. In all, the plasmaproteins have been reduced below the normallevel. Though many of them have infections,often caused by hemolytic streptococci, the localreaction to the infection is sluggish, and, as hasbeen pointed out by Winkenwerder, McLeod andBaker (5), the onset of the disease, being insidi-ous, is quite different from that observed in thepatients grouped in Type A. It is possible thatthe reactive processes of the body are partiallysuppressed in this group. This might result in

an ineffective reaction against the infection as wellas against the lesions in the kidney; and the lowtiters of antistreptolysin may be actually anotherindication of the lack of response of the pro-tective mechanism. Another explanation mightbe found in the possibility that the infection andthe accompanying nephritis is primarily associatedwith an organism other than the hemolytic strep-tococcus. Rake and Blackman (7) have recentlyrecalled attention to the fact that acute hemor-rhagic nephritis may occur as a result of infec-tions by pneumococci, and Seegal (8) supportsthis view. Blackman (9) has been able to pro-duce experimentally in rabbits through the re-peated intravenous injection of pneumococcustoxin a form of nephritis accompanied by edema.

It might be argued, therefore, that the hemo-lytic streptococci occur in these patients acci-dentally, or as an inactive associated organism,and thus cannot be regarded as the immediatecause of the infection. The fact remains, how-ever, that in at least one patient a severe tonsil-litis due to hemolytic streptococci was not fol-lowed by a rise in titer above normal.

Discussion of the conditions in the third groupis not necessary, since there was no indication thatthe various forms of disease of the kidney werein any way connected with infections due tohemolytic streptococci.

DISCUSSION

The observations that we have made accordwith those of others, and add further evidence toshow that infections by hemolytic streptococci aresometimes accompanied, but are more often fol-lowed, by a significant rise in the antistreptolysincontent of the blood serum. The rise does notusually occur until one to three weeks after theonset of the infection. It reaches its highest titerpromptly, and, then, after a variable length oftime, falls sometimes rapidly but frequentlyslowly to the normal level. The period duringwhich the antistreptolysin titer persists at an ab-normally high level is extremely variable. Thetiter does not always fall immediately with recov-ery from the disease, for high titers may be en-countered for weeks or months after the patientis entirely well. This may occur following mildas well as severe infections. On this account, if

290

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOOD SERUM. II

for no other reason, the test cannot be employedfor diagnostic purposes, unless the actual changefrom a normal titer to a high titer occurs underobservation.

The height to which the antistreptolysin titerrises does not seem regularly to be dependentupon the severity of the infection. Indeed as wasfirst noted by Todd (1), fatal infections by hemo-lytic streptococci may not be accompanied by anyincrease in the antistreptolysin content of theblood. Coburn and Pauli (2) have, however,presented evidence to show that the height of theantistreptolysin titer parallels to a certain extentthe severity and duration of acute attacks of rheu-matic fever, but this has not been the usual ex-perience with streptococcal infections in general,nor has it occurred in our small series of cases.

There appears, also, to be some variation in theproduction of abnormal amounts of antistrepto-lysin in different forms of streptococcal infection.In our series, increase in antistreptolysin fre-quently did not occur after acute tonsillitis andpharyngitis, and in the patients in which the anti-streptolysin did increase it rarely reached a hightiter. Coburn and Pauli (2) have called atten-tion to this same occurrence in their series. Anincreased antistreptolysin was more common inscarlatina and high titers more frequent, whileantistreptolysin was regularly increased in ery-sipelas, and high titers were the rule. Underthese circumstances it appears somewhat peculiarthat in rheumatic fever and hemorrhagic nephri-tis, both of which are so commonly preceded byacute streptococcal tonsillitis and pharyngitis, theantistreptolysin should be so regularly elevated toa high titer during the acute stage of the disease.

One might advance this as an argument touphold the view that both diseases are caused byhemolytic streptococci, but it is obvious, from theprevious experiences, that persistently high titersof antistreptolysin may be obtained for weeks fol-lowing all varieties of streptococcal infection.This raises a valid objection to using this test asan indication that any complication of a strepto-coccal infection is in itself due to hemolytic strep-tococci. The observations can undoubtedly beinterpreted, however, as meaning that both dis-eases are preceded with remarkable constancy byinfections due to hemolytic streptococci, but

scarcely warrant any further conclusion in regardto the etiology of acute hemorrhagic nephritis oracute rheumatic fever.

It seems probable that other explanations maybe offered to account for the regularity of therelatively high antistreptolysin in these conditions.

In the first place, it is possible that certainstrains of hemolytic streptococci may call forththe production of greater amounts of antistrepto-lysin than others. There is, however, no directevidence that would uphold this view.

In the second place, it is conceivable that thereactive processes of different individuals may notrespond either qualitatively or quantitatively inthe same way to a similar stimulus. Under suchcircumstances there might be a wide variation inthe frequency with which increased amounts ofantistreptolysin appeared in the serum and in theheight to which it rose in different forms of strep-tococcal infections. The differences, under thesecircumstances, would depend less upon the formof infection than upon the peculiar reaction of theindividual to this infection. Such an interpreta-tion would accord very well with the observationsmade upon the two forms of nephritis designatedas A and B. In the first type, high titers werethe rule; in the second type, high titers were prac-tically absent, and even when in the Type B casesthe titrations were made during and following anexacerbation of nephritis coincident with a severetonsillitis due to B. hemolytic streptococci, an in-crease in the titer above normal was not observed.

If further studies show that the observations al-ready recorded occur with considerable constancy,they would still further support the view that theformation of antistreptolysin reflects the degreeto which the reactive processes of the body re-spond in certain forms of streptococcal infectionsor in some diseases following streptococcal in-fections. It might be found that the response ofthis particular antibody is exaggerated in ery-sipelas,4 scarlatina, rheumatic fever and in oneform of acute hemorrhagic nephritis. It is to beremarked that in all of these diseases an allergic

4 Spink and Keefer have recently published data toshow that the antistreptolysin content of the serum frompatients with erysipelas, increased regularly and oftenrose to a very high titer within the first 20 days afterthe onset of the illness. High titers persisted for periodsof 40 days to 6 months.

291

WARFIELD T. LONGCOPE

factor is considered by many to play a nmore orless definite part in the pathogenesis and naturalhistory of the process. There is no particularreason, however, to suppose that the allergic fac-tor and the antistreptolysin response are in anyway related.

CONCLUSIONS

1. Repeated determinations of the antistrepto-lysin content of the serum from normal indi-viduals and from patients suffering from a vari-ety of chronic diseases unrelated to streptococcalinfections showed that the titer in the majority ofcases fell between 25 and 50 units and rarely ex-ceeded 100 units.

2. In acute infections, due to agents other thanhemolytic streptococci, titers above 100 units wereencountered a little more frequently (22.7 percent of 66 cases).

3. Significant increases in antistreptolysin werefound in the serum from patients with strepto-coccal infections. This occurred in order of fre-quency and in height of elevation in acute tonsil-litis and pharyngitis, in miscellaneous infections,in scarlet fever, erysipelas and rheumatic fever.In acute rheumatic fever the antistreptolysin titerswere regularly and markedly increased.

4. High antistreptolysin titers were also ob-tained regularly in one form of acute hemorrhagicnephritis designated as Type A. In a secondform, also preceded by streptococcic infections,designated Type B, but with insidious onset, theantistreptolysin titers were rarely above the nor-mal and were in some patients unusually low.

5. Though some correlation could be noted be-tween the antistreptolysin curves and the courseof the disease in patients with acute rheumatic fe-ver and with acute hemorrhagic nephritis, this wasnot very close.

6. Reasons are given for concluding that theoccurrence almost constantly of the high anti-streptolysin titers that are observed during thecourse of acute rheumatic fever and acute hemor-rhagic nephritis, only indicate the recent occur-rence of an infection due to hemolytic strepto-cocci and cannot be used as evidence that thesediseases are caused by hemolytic streptococci.

7. There appears to be a difference of reac-tivity amongst individuals suffering from differ-ent forms of streptococcal infections. This leads

to variation in the production of antistreptolysin.8. Patients suffering from acute rheumatic fe-

ver and from acute hemorrhagic nephritis (TypeA) appear to be especially prone to the formationof antistreptolysin in comparatively large quanti-ties.

I am indebted to Miss Anne Austin McLana-han for assistance in compiling the tables.

PROTOCOLS

Number 11. Antistreptolysin first determined January20, fourteenth day of disease. Male, colored, age 32.Admitted J. H. H. January 18, 1933, with pain in chestand swelling of eyes. Always well until December 26,1932, when he developed erysipelas, complicating epidemicparotitis. During acute attack urine normal. On Janu-ary 6, trace of albumin in urine; on January 12, swellingof ankles, pain in side, shortness of breath. On admis-sion, anasarca, rales at bases of lungs, slight enlargementof heart, blood pressure 170/100, exudates and hemor-rhages in retinae, leukocytes 5,850, albuminuria, cylin-druria and marked hematuria; phthalein 65 per cent;N.P.N. 28. Urea clearance 40 per cent normal maxi-mum. Albumin and red blood cells in urine diminishedrapidly. Discharged April 5. No edema, blood pres-sure 120/90, phthalein 80 per cent, N.P.N. 30, ureaclearance 91 per cent normal maximum, urine con-centrated specimen (Addis count) albumin trace, redblood cells diminished from 21 million to 2.5 million.April 19, 1934, readmitted to hospital with generalizedinfection by Bacillus suipestifer. Recovered after febrileillness of 18 days. During illness urine showed no albu-min, no red blood cells, no casts. May 10, 1934, Addiscount-specific gravity 1,027, protein 40, red blood cells300,000, leukocytes 1,000,000, no casts, phthalein 78 percent, urea clearance 130 per cent normal standard. Bloodpressure 110/82 to 95/65.

Number 20. Antistreptolysin first determined April 10,fifth day of disease. Male, white, age 16. Admitted toJ. H. H. April 8, 1933, with swelling of face and anklesfor 3 days. In November, 1932, appendectomy; bloodpressure 90/70. Urine normal. On March 16, 1933,scarlatina. On April 5, 1933, 20 days later, swelling offace, ankles, headache, vomiting, frequency of urinationand some fever. On admission, third day of illness, tem-perature 101.6°, anasarca, pleural effusion, hemorrhage inretina, swollen tonsils, presystolic gallop rhythm. Bloodpressure 180/115, leukocytes 9,100. Urine smoky, albu-min 0.6 per cent, many red blood cells, leukocytes andcasts. Cultures from pharynx-B. hemolytic streptococ-cus +++, phthalein 80 per cent, N.P.N. 30. Rapid im-provement. April 13, blood pressure 136/80, loss ofedema with diuresis. Discharged May 28, 1933, symp-tomatically well. Blood pressure 110/64, phthalein 70per cent, N.P.N. 33, urea clearance 65 per cent normalstandard. Concentrated specimen of urine (Addis count)

292

VARIATIONS IN ANTISTREPTOLYSIN TITER OF BLOOD SERUM. II

normal. December 4, 1933, tonsillectomy. Blood pres-sure 115/70, phthalein 70 per cent, urea clearance 120 percent normal standard. Urine concentration 1,016 to1,030. December 15, 1933, Addis count-specific gravity1,030, protein 34, red blood cells 1,700,000, casts 3,000.January 25, 1934, blood pressure 110/70. Urine-no al-bumin, red blood cells, or casts. Well. December 19,1934, blood pressure 120/74. Urine-no albumin, nocasts, no red blood cells. October 9, 1935-urine, no al-bumin, no casts, no red blood cells.

Number 23. Antistreptolysin first determined Janu-ary 29, tenth day of disease. Female, colored, age 21.Admitted to J. H. H. January 28, 1935. Past health ex-cellent. On January 5, 1935, severe cold and sore throat,followed by cough and swelling of legs and abdomen onJanuary 19, 1935. A few days later nausea, vomiting,headache, nocturia and generalized edema. On examina-tion, pallor, anasarca, exudate over enlarged tonsils, bi-lateral hydrothorax, enlargement of cardiac dullness, sys-tolic murmur. Blood pressure 158/110, edema of retina,enlargement of liver and spleen and ascites. Urine clear,specific gravity 1,012, acid, albumin +, hyaline and gran-ular casts ++, red blood cells +++, leukocytes +++.Cultures from tonsils B. hemolytic streptococcus +++.Phthalein 40 per cent, N.P.N. 30, urea clearance 42 percent normal standard. Rapid improvement with loss ofedema, fall of blood pressure and diminished albuminuriawithin 10 days. March 9, tonsillectomy without reaction.Discharged March 23, without edema, traces of albuminand a few red blood cells in urine. Blood pressure 90/60,phthalein 90 per cent, urea clearance 78 per cent normalstandard. April 3, 1935, the physical examination andurine showed nothing abnormal. Blood pressure 104/66.Urine concentrated specimen-acid, albumin trace, nocasts, no red blood cells. November 27, 1935, perfectlywell. Blood pressure 104/70. Urine showed no albumin,no casts, no red blood cells.

Number 19. Antistreptolysin first determined March19, second month of disease. Male, white, age 33. Ad-mitted to J. H. H. March 18, 1934, with fistula in ano,localized dermatitis, albuminuria and hematuria. Exces-sive alcohol. For 2 years, frequent "boils"; for 9months local infection on left arm. Five months ago,swelling of face; 2 months later blood pressure found tobe high and urine to contain albumin and blood. On ad-mission, pasty, face slightly puffy, heart slightly enlarged.Blood pressure 142/90, perianal scars, elevated red granu-lating lesion 3 X 5 cm. on left arm, cultures from whichshow numerous B. hemolytic streptococcus in pure cul-ture. Hemoglobin 72 per cent, red blood cells 3,800,000;leukocytes 8,100. Urine: specific gravity 1,010, albumin+, red blood cells ++++, casts ++. Phthalein 48per cent, N.P.N. 34; urea clearance 62 per cent normalstandard. Removal of infection on arm. DischargedJune 23, 1934, condition unchanged. Blood pressure138/95. General health after discharge good, but albu-minuria and hematuria persisted. April 24, 1935, noedema, color good. Operative wound healed. Bloodpressure 155/105. Phthalein 70 per cent; urea clearance

73 per cent normal standard. Urine: specific gravity1,025 to 1,037, albumin ++, many red blood cells andcasts.

Number 27. Antistreptolysin first determined Novem-ber 14, 1932, third month of disease. Male, white, age 27.Admitted to J. H. H. November 9, 1932, with swelling offace and ankles, vomiting and bloody urine. Rheumaticfever at 15; chronic discharging ear for 20 years. InAugust, 1932, severe sore throat with fever; two weekslater vomiting and abdominal pain, followed after a weekby swelling of face and feet, with bloody urine. Sinceonset swelling has decreased but bloody urine continues.On admission, no edema, discharging right ear, presys-tolic gallop rhythm. Blood pressure 138/84. Right kid-ney palpable. Leukocytes 6,600. Urine: smoky, albumin0.6 per cent, grossly bloody, many leukocytes and casts.Phthalein 55 per cent. Culture of sputum B. hemolyticstreptococcus. Discharged in practically the same con-dition. December 22, 1932-remains symptomaticallywell, but persistent albuminuria and hematuria. Decem-ber 5, 1934-blood pressure 128/88, N.P.N. 36; ureaclearance 105 per cent normal standard, total blood pro-tein 6.5 grams per liter. Phthalein 75 per cent. Urine:specific gravity 1,007 to 1,023. Urine concentrated (Ad-dis count) protein 147 mgm., red blood cells 6,000,000,casts 700,000. May 1, 1935, symptomatically well. Bloodpressure 128/74. Urine: albumin +, hyaline and granu-lar casts +, red blood cells ++ +.

Number 31. Antistreptolysin first determined Novem-ber 14, fourth day of disease. Female, white, age 18.Admifted to J. H. H. November 13, 1932, with backache,fever and bloody urine. Always healthy, no previousinfections. Seven days before admission, pain in back;3 days later, chills, vomiting; next day, headache, anuriaand then bloody urine, cough, fever. On admission, tem-perature 102.40 F., looks ill, face puffy, swollen tonsils.Solidification left lower lobe, bilateral costovertebral ten-derness. Blood pressure 110/70. Edema over tibia.Leukocytes 5,000. Urine: albumin +++, red bloodcells ++++, leukocytes and casts +++. N.P.N. 120.Culture from throat: many B. hemolytic streptococcus.Sputum: many B. hemolytic streptococcus, and pneumo-coccus Group IV. After first week, improvement in gen-eral condition, but appearance of generalized rash lasting3 days, rise in blood pressure to 140/100; phthalein 30per cent. By December 5th, gradual decrease in N.P.N.to 36, and of blood pressure to 125/90. Later slow im-provement and on discharge February 15, 1933, urineshowed only trace of albumin, occasional red blood cellsand few casts. Phthalein 80 per cent. In good physicalcondition, but albuminuria, hematuria and cylindruriapersist up to January 1, 1934, when, after severe attackof tonsillitis due to B. hemolytic streptococcus, edemaappeared, albumin, red blood cells and casts increased inurine. N.P.N. rose to 108 on January 5, and phthaleinfell to 4 per cent; blood pressure 108/68. Gradual im-provement. Tonsillectomy February 15, followed by in-creased albuminuria, hematuria and cylindruria. Janu-ary 8, 1936, symptomatically well. Blood pressure

293

WARFIELD T. LONGCOPE

110/70. Urine: pale, albumin questionable, occasionalred blood cells and leukocytes, no casts.

BIBLIOGRAPHY

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