CHAPTER XV
Diseases of the Blood and Blood-Forming Organs
Maurice B. Strauss, M.D.
Disorders of the hematopoietic and lymphatic systems did notconstitute a major problem of the Medical Department during World War II.Nevertheless, over 7 percent of all accessions to the Army Institute ofPathology, Washington, D.C., received between 7 December 1941 and 2 September1945, numbering almost 5,000 specimens, were classified under this heading.1For many of the diseases under consideration, the problems of diagnosis,treatment, and ultimate prognosis differed in no significant way from the sameproblems in civilian life. However, the experience of the members of the MedicalDepartment revealed eight noteworthy observations in this field, as follows:
1. Severe anemia (p. 398) was rarely encountered amongsoldiers who had had repeated attacks of malaria in contrast to its frequentoccurrence in infected civilian populations.
2. Although hookworm infection (p. 398) was common in certainareas where U.S. troops were stationed, severe anemia-the outstanding cause ofdisability in hookworm disease in civilians-was rare.
3. Eosinophilia (p. 399) as high as from 67 to 83 percent,with total leukocytes numbering between 50,000 and 60,000, were encountered inboth hookworm infection and schistosomiasis and sometimes created a diagnosticproblem in differentiation from eosinophilic leukemia.
4. In a small number of cases, Atabrine (quinacrinehydrochloride) was implicated as a causative factor in apalstic anemia (pp.401-404).
5. Infectious mononucleosis (p. 405) was recognized in troopsmore often than in civilian populations and at times reached minor epidemicproportions. Spontaneous rupture of the spleen was observed at least seven timesin infectious mononucleosis.
6. Despite the liberal and widespread use of sulfonamidedrugs, agranulocytosis (p. 406) was uncommon and rarely fatal.
7. Nitrogen mustard (p. 406), a chemical warfare agent, wasshown to have much promise in the treatment of lymphomatous disease.
1Custer, R. P., and Miller, M. H.: Lymphatic and Hematopoietic Disease in the United States Army During World War II: General Survey and Consideration of Histopathologic Diagnosis. [Professional paper.]
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8. Aplastic anemia (p. 412) was produced in a goodly numberof individuals exposed to irradiation from atomic bomb explosions at Hiroshimaand at Nagasaki, Japan.
SEVERE ANEMIA
Anemia due to the destruction of parasitized erythrocytes waspresent to some degree in all cases of malaria. A single severe paroxysm offalciparum malaria might reduce the number of erythrocytes by 1 million cellsper cubic millimeter. Although such severe hemolysis was uncommon in vivaxinfections, a significant degree of anemia frequently occurred. It is thereforeof interest that anemia from malaria was so rarely encountered among the troopsof the United States. In part, this may be explained by the fact that treatmentwas generally prompt so that repeated paroxysms did not occur in any singleattack, although recurrent attacks were general. Of 435 soldiers evacuated fromislands in the South Pacific Area and admitted to Harmon General Hospital,Longview, Tex., with recurrent malaria, the average number of attacks beforeadmission was 5.7.2 Of these 435 soldiers,there were 287 whose records contained adequate data on the hematopoieticstatus. Only three patients had less than 13.0 gm. and only 26 had less than14.0 gm. of hemoglobin per 100 cc. of blood. The erythrocytes of seven mennumbered less than 4.0 million per cubic millimeter and in 72 men the number wasunder 4.5 million per cubic millimeter. In connection with this conspicuousabsence of anemia, it may be mentioned that the spleen was palpable in only 23percent of the acute attacks, and then only transiently. This also may berelated to the prompt institution of therapy in each attack.
HOOKWORM INFECTION
Hookworm infection3 wasacquired by a goodly number of troops in the combat areas of the Pacific.However, signs or symptoms (other than eosinophilia) which could be attributedto the infection alone were almost never found. Among civilian populations withhookworm infection, hypochromic anemia is the outstanding feature and, in amajority of patients, is the chief cause of disability. Rhoads, Castle, Payne,and Lawson4 clearly showed (1) that this anemiais due to a deficiency of iron brought about by the chronic loss of blood, bydefective diets, and by gastrointestinal changes; (2) that it may be correctedby therapy with iron without removing the
2Gordon, H. H., Lippincott, S. W., Marble, A., Ball, A. L., Ellerbrook, L. D., and Glass, E. W., Jr: Clinical Features of Relapsing Plasmodium Vivax Malaria in Soldiers Evacuated From the South Pacific Area. Arch. Int. Med. 75: 159-167, March 1945.
3See also chapter V, pp. 146-153.
4Rhoads, C. P., Castle, W. B., Payne, G. C., and Lawson, H. A.: Hookworm Anemia; Etiology and Treatment With Especial Reference to Iron. Am. J. Hyg. 20: 291-306, 1934.
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parasites; and (3) that the removal of the hookworms does notcause a prompt remission of the anemia. Although a great many writers indicate abelief that the presence or absence of anemia in hookworm infection depends onthe number of worms, Scott5 points out that itis the host's reserves of iron that determine the onset and degree of theanemia. Two studies are available among troops infected with hookworm-hemoglobinand determination of the number of erythrocytes. In 100 malarial and surgicalpatients infected with hookworm, not a single case had signs or symptoms whichcould be attributed to the infection alone, and only 10 patients had fewer than4.0 million erythrocytes per cubic millimeter. In these, the anemia could berelated to other causes.6 Examinations of theblood of 1,000 soldiers, 93 of whom had hookworm infection and 907 of whom didnot, showed that 19 men (20 percent) of the infected patients had fewer than 4.0million erythrocytes per cubic millimeter and that 34 percent had less than 80percent hemoglobin. In the nonparasitized group, 15 percent had fewer than 4.0million erythrocytes per cubic millimeter and 37 percent less than 80 percenthemoglobin. The smallest number of erythrocytes encountered was 3.1 million percubic millimeter and the lowest hemoglobin was 60 percent.7Although it is probable that the infection of troops was not heavy, thegeneral absence of signs and symptoms-and of anemia-can best be ascribed tothe excellent nutritional state of the men and the adequacy of their diet.
EOSINOPHILIA
Eosinophilia of moderate degree in both hookworm infectionand schistosomiasis has long been recognized. Extreme eosinophilia is mentionedin many textbooks on these disorders. Ashford, Payne, and Payne, in 1933,8reported a case of uncinariasis with 87 percent eosinophils and a total count of41,200 leukocytes per cubic millimeter and another case with a total count of78,400 leukocytes per cubic millimeter, 68 percent of which were eosinophils.
Among troops, it was noted that both eosinophilia andleukocytosis generally reached a maximum between 3 and 4 months after hookworminfection.9 The highest percentage ofeosinophils was 67 percent of 28,000 leukocytes; the highest number was 47,000in a patient with 48 percent eosinophils. Eosinophilia may persist for a year ormore, although the
5Scott, J. A.: Iron-Deficiency Anaemias. Lancet 1: 357, 549, 1938; also Am. J. Hyg. 26: 455-505, 1937.
6Most, H., Hayman, J. M., Jr., and Wilson, T. B.: Hookworm Infections in Troops Returning from the Pacific. Am. J.M. Sc. 212: 347-350, September 1946.
7Essential Technical Medical Data, U.S. Army Forces, South Pacific Area, dated 1 Feb. 1944.
8Ashford, B. D., Payne, G. C., and Payne, F. K.: Acute Uncinariasis From Massive Infestation and its Implications. J.A.M.A. 101: 843-847, 1933.
9(1) Liebow, A. A., and Hannum, C. A.: Eosinophilia, Ancylostomiasis, and Strongyloidosis in the South Pacific Area. Yale J. Biol. & Med. 18: 381-403, May 1946. (2) Whitehouse, F. R.: Massive Eosinophilia in Uncinariasis; Report of Two Cases. Gastroenterology 9: 303-306, September 1947.
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leukocytosis generally disappears sooner. It should bepointed out that both leukocytosis and eosinophilia of marked degree may occurbefore hookworm ova can be demonstrated in the stools, thereby creating adiagnostic problem. L?ffler's syndrome, tropical eosinophilia, andeosinophilic lung, which were reported, may well represent instances of hookworminfection or of schistosomiasis. Wright and Gold10have reported from Camp Blanding, Fla., nine cases of creeping eruption (causedby Ancylostoma braziliense) with transient migratory pulmonaryinfiltration and eosinophilia. In schistosomiasis, Billings and his coworkers11reported 83 percent eosinophils in a patient whose total leukocytes numbered53,000 per cubic millimeter. Mason and his coworkers12noted that 14 percent of their 300 cases of schistosomiasis had over 70 percenteosinophils and that 32 percent had between 50 and 70 percent eosinophils. Ofthe 300 patients, 8 percent had leukocytes numbering between 30,000 and 60,000and 25 percent had between 20,000 and 30,000. Thus, it is apparent that bothhookworm infection and schistosomiasis may present a picture of the bloodsuggestive of eosinophilic leukemia.
MALARIA
It was pointed out by Lt. Col. Richard P. Custer, MC, of theArmy Institute of Pathology,13 that,during the first year of the war in the Pacific, bitter experience proved thatmalaria could neutralize U.S. combat forces more rapidly and more effectivelythan enemy fire. Guadalcanal, New Guinea, and certain areas of theChina-Burma-India theater were among the most highly malarious regions of theworld. Control measures for malaria could not be put into effect so long as themilitary situation remained unstabilized and U.S. soldiers were living andfighting in the jungle. Although mosquito repellents and protective clothingafforded a small measure of protection, it was not until control of malaria bysuppressive-drug therapy was introduced in November 1942 in Guadalcanal, andsubsequently employed in New Guinea, that the inroads of the disease began todiminish.14 Within a year after thebeginning of suppressive-drug therapy, its value was so thoroughly establishedthat it was intensively used in all malarious regions of the Pacific. Thisintensive use began in November 1942.
During the next year, medical officers in the SouthwestPacific Area called attention to a characteristic cutaneous lesion which wasoccurring in
10Wright, D. O., and Gold, E. M.: Loeffler's Syndrome Associated With Creeping Eruption (Cutaneous Helminthiasis). J.A.M.A. 128: 1082-1083, 11 Aug. 1945.
11Billings, F. T., Winkenwerder, W. L., and Hunninen, A. V.: Studies on Acute Schistosomiasis in Philippine Islands; Clinical Study of 337 Cases With a Preliminary Report on Results of Treatment With Fuadin in 110 Cases. Bull. Johns Hopkins Hosp. 78: 21-56, January 1946.
12Mason, P. K., Daniels, W. B., Paddock, F. K., and Gordon, H. H.: Latent Phases of Asiatic Schistosomiasis. Arch. Int. Med. 78: 662 -678, December 1946.
13Custer, R. P.: Aplastic Anemia in Soldiers Treated With Atabrine (Quinacrine). Am. J.M. Sc. 212: 211-224, August 1946.
14Dieuaide, F. R.: Personal communication.
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soldiers who had been evacuated from New Guinea and adjacentislands.15 This lesion, termed "atypicallichen planus," but which also included eczematoid reactions, wasassociated with Atabrine therapy so frequently that an etiological relationbetween the drug and the skin lesion seemed probable.
During 1943 and 1944, it was noted that the incidence ofaplastic anemia in the Southwest Pacific and the South Pacific Areas and in theChina-Burma-India theater was considerably higher than in all the other foreigntheaters and also higher than in the continental United States.16A study of aplastic anemia made at the Army Institute of Pathology is quiterevealing (chart 4). Throughout the entire period from January 1942
CHART 4.-Incidenceof aplastic anemia among U.S. Army troops, 1942-45
to June 1945, the incidence of aplastic anemia in the entireArmy-exclusive of the South Pacific, Southwest Pacific, and China-Burma-India-remainedbelow 0.18 cases per 100,000 troops; whereas, in the areas just cited, it rosesteadily from early 1943 to the end of 1944, reaching a peak of 2.84 cases per100,000 troops in the period from July to December 1944, at a time when the ratefor the rest of the Army was 0.04 cases per 100,000.
15Bull. U.S. Army M. Dept. 4: 653-659, December 1945.
16See footnote 13, p. 400.
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The beginning of this increased incidence in the SouthPacific and Southwest Pacific Areas and in the China-Burma-India theater in 1943coincided with the period of the increased use of Atabrine in these areas. Thepeak in 1944 coincided with the period when suppressive-drug therapy was inextensive and widespread use. The incomplete figures for the first half of 1945are of dubious significance. If borne out by complete data, they might reflectthe diminished use of Atabrine as other measures to control malaria becameeffective and might reflect as well a smaller number of persons taking Atabrineas a result of troops being moved out of the more malarious areas in thesetheaters.
The cases of aplastic anemia occurring in 1943 and 1944 werefurther analyzed.17 Among the 20cases from nonmalarious regions, 2 followed arsenical treatment for syphilis, 3occurred after irradiation of malignant tumors, 4 were ascribed to sulfonamidemedication, and in 11 patients no cause could be demonstrated. The 47 cases thatoccurred in the South Pacific and Southwest Pacific Areas and in theChina-Burma-India theater had all received suppressive doses of Atabrine overperiods ranging from 1 to 34 months; the majority ranged between 4 and 9 months.The 34-month case was unique, however, and the patient apparently had notadhered to the prescribed regimen, as his record showed repeated attacks oftertian malaria which required active treatment.
There was specific mention of overdosagebefore the onset of illness in six cases. Four men had increased the dose to 0.2gm. daily, one for 3 weeks, another for 6 months, a third for 8 months, and thelast for an unspecified time. Another soldier took between 20 and 30 tabletsduring the 4 days preceding onset of symptoms; still another was said to haveingested massive doses for 3 weeks before. Other instances of overdosageprobably occurred, but were either not known or not recorded. For example, menon patrol or detached service were given supplies of Atabrine adequate forestimated time away from their units and, although instructions in its use weregiven, its administration was unsupervised.
Seven of the group treated with Atabrine hadalso taken sulfathiazole or sulfadiazine. In two instances, it was not possibleto exclude sulfonamide drugs as a precipitating factor, but in the others it wasobvious that the drugs were administered only after the onset of the anemia andin two cases aggravated the purpuric manifestations.
Atabrine dermatitis complex, the term proposed to designateatypical lichen planus, preceded aplastic anemia in 20 patients. In these,topical applications of various sorts were used-and light roentgenologictreatment was given in one instance-but were not regarded as significantcausal factors.
A few patients had taken aspirin for headache,which was frequently a feature of the prodromal period. The others had receivedno drugs, nor could a history of exposure to other etiological agents beelicited.
The study of case records of soldiers who developed aplasticanemia after taking Atabrine revealed no significant differences in themanifestations from those encountered in aplastic anemias of varied etiology.
17See footnote 13, p. 400.
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The most common complaint of the prodromalperiod was weakness, often associated with headache, vertigo, and dyspnea. Ahemorrhagic tendency was frequently noted early, evidenced by bleeding gumsafter brushing teeth, nosebleed, "bruising easily," or the spontaneousappearance of ecchymoses in the skin. Dimness of vision, noted first by two ofthe patients, was found to be the result of intraocular hemorrhage. In themajority of cases, the onset was gradual, several weeks to a month or even moreelapsing before the man reported to sick call. The prodrome was of briefduration in six cases and the onset precipitous in three in which an acutefebrile state was the first indication of illness.
The early manifestations of aplastic anemiawere often unnoticed in the group of 25 patients who were being treated for skinlesions until individuals among them were observed to be rather pallid and ablood count disclosed a reduction in the formed elements of the blood. In noinstance did the anemia precede the dermatitis.
Almost invariably the course was marked by fever andhemorrhagic phenomena, the location and extent of the hemorrhages accounting fordifferences in symptoms. For example, hemiplegia, convulsions, and coma werenoted in patients with intracranial bleeding; in contrast, hematuria andsometimes pain were associated with hemorrhage of the urinary tract. Of fourpatients, one was known to have survived at least 2 months; a second, 4 months;and the other two, 7 months.
Hematological findings-Rather complete series of bloodcounts were submitted in most cases, and the diagnosis of aplastic anemia wasconfirmed by sternal biopsy in 25.
In four patients, blood counts were performed very soon afterthe onset and showed that the number of erythrocytes was fairly well maintained(4.0 to 5.0 million per cubic millimeter), whereas the numbers of leukocytes andplatelets had fallen sharply, the lowest being 1,500 and 40,000 per cubicmillimeter, respectively. This is to be expected when one recalls the relativelylong life (120 days or more for erythrocytes as opposed to from 3 to 5 days forneutrophils and platelets) of the mature erythrocytes and that most of theresidual cells found in the bone marrow at necropsy are their progenitors.
The other 21 patients were already anemic when firstexamined, and initially the erythrocytes numbered as few as 600,000 per cubicmillimeter, although the average range was from 1.5 to 3.0 million per cubicmillimeter. The anemia was generally of the normocytic, normochromic type. Insome cases, it seemed to be macrocytic, but this is questionable since it wasreported only in instances where the anemia was severe; that is, in the rangewhere hemoglobin readings are apt to be very inaccurate. Furthermore, nohematocrit values were available in these cases as a check on the presence ofmacrocytosis. Nucleated erythrocytes almost never appeared in the peripheralblood. Reticulocyte counts over 1 percent were rarely recorded and they werefrequently reported as either none or less than 0.1 percent. Anisocytosis andpoikilocytosis were seldom marked except in the few cases showing evidence ofregeneration. It was possible with frequently repeated blood transfusions torestore the number of erythrocytes and the amount of hemoglobin to normal ornearly so in 16 patients and to effect
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an improvement in nearly all. A few patients becameprogressively more anemic despite transfusions, and the majority did notmaintain their improved status.
The initial leukocyte count was seldom over3,000 per cubic millimeter and usually fell between 1,000 and 3,000 being normal(7,200) in only one case. Values below 1,000 per cubic millimeter were noted infive instances. The counts fluctuated somewhat, and occasionally rose followingtransfusions, but the general trend was toward lower levels as the diseaseprogressed, with little tendency to increase significantly even during clinicalremissions. The leukopenia was due primarily to failure of the bone marrow toproduce granulocytes, but when the total count was greatly reduced the relativelymphocytosis actually represented a lymphocytopenia. This was also the casewith respect to the monocytes. Absolute agranulocytosis was frequently recorded,but a general scan of the blood films usually disclosed a few neutrophils, mostof them mature forms. Immature granulocytes were occasionally seen early in thecourse of the disease, but rarely thereafter.
The number of platelets was significantly low in all but 4 ofthe 49 cases in which counts were done. In three of these exceptions, theplatelets were counted once and it was then early in the course of the disease.In the fourth, two counts were recorded as 263,000 and 154,000 per cubicmillimeter. Necropsy disclosed extensive visceral hemorrhages in every one ofthese cases, however, and the marrows were devoid of megakaryocytes, indicatingthat platelets must have been subsequently much reduced. In general, the countsranged between zero and 100,000 per cubic millimeter, with most of them below50,000 at some time during the disease.
The coagulation time of the blood was but little altered, butclot retraction was either slow or absent. Bleeding time was sometimes normaleven though the tourniquet test was positive. In other cases, the bleeding timewas prolonged; in one patient, blood oozed for several days from the prickcaused by the lancet.
Examination of the bone marrow in all cases showed the marrowto be markedly depleted of all normal hematopoietic elements. Usually theresidual cells of the marrow belonged to the erythropoietic series and were inthe late erythroblastic and normoblastic stages. The few granulocytes weregenerally stab or segmented forms, although occasionally small foci ofmyelocytes or even younger elements were encountered. Megakaryocytes were eitherabsent or very sparsely distributed and when present often showed evidence ofdegeneration.
Although the evidence now makes it appear that Atabrine wasetiologically significant in the production of bone marrow aplasia, it must bepointed out most emphatically that even the highest rate, 2.84 cases of aplasticanemia per 100,000 troops, was of trivial significance in comparison with bothmalarial morbidity and mortality before the introduction of suppressive-drugtherapy.
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INFECTIOUS MONONUCLEOSIS
Infectious mononucleosis has been a commonly diagnoseddisorder among troops both in the continental United States and in theatersoverseas. During 1944, the rate of admission for this disease was 97 per 100,000troop strength. This high incidence of the disease may be explained by a numberof factors. First, a routine examination of the blood was made on all Armypatients admitted to hospitals, while in civilian life many of these patientswould have been treated at home without the benefit of a hematological studyand, therefore, their disease would have gone undiagnosed. Secondly, infectiousmononucleosis is a disease which has the highest incidence in youth.
Contratto18 foundthat 1.5 percent of the total medical admissions to Stillman Infirmary, HarvardUniversity, Cambridge, Mass., were due to mononucleosis, whereas only 0.36percent of the total medical admission to the Peter Bent Brigham Hospital,Boston, Mass., were so diagnosed. The disease was definitely epidemic in certainareas. In the Caribbean Defense Command during the last 4 months of 1944, 92cases of infectious mononucleosis were admitted to the 368th Station and the262d General Hospitals.19 In theUnited States, 300 cases were observed within a period of 20 months at severallarge hospitals of the Army Air Forces.20 Atthe Station Hospital, Camp McCoy, Wis., between December 1943 and May 1944, 340subclinical cases were discovered while 26 clinical cases were being treated.21
No evidence was accumulated during the war which wouldindicate that the severity of infectious mononucleosis was increased when itappeared in epidemic form. However, spontaneous rupture of the spleen, acomplication which has been reported only three times in civilian life,22occurred at least seven times in the Army.23 Atotal of 44 instances of spontaneous rupture of the spleen have been collectedby the Army Institute of Pathology from 7 December 1941 to 2 September 1945.24The cause of rupture could not be determined in 5 patients; in 22, it was due tomalaria; in 7, to mononucleosis; in 5, chronic congestive splenomegaly (Banti'ssyndrome); in 3, to torsion; and in 2, to leukemia.
18Contratto, A. W.: Infectious Mononucleosis; A Study of One Hundred and Ninety-Six Cases. Arch. Int. Med. 73: 449-459, June 1944.
19Essential Technical Medical Data, Caribbean Defense Command, for January 1945, dated 20 Feb. 1945. Inclosure 1, "Epidemic of Infectious Mononucleosis."
20Read, J. T., and Helwig, F. C.: Infectious Mononucleosis; An Analysis of Three Hundred Cases With Three Characterized by Rare Hematologic Features. Arch. Int. Med. 75: 376-380, June 1945.
21Vander Meer, R., Lutterloh, C. H., and Pilot, J.: Infectious Mononucleosis; Analysis of 26 Clinical and 340 Subclinical Cases. Am. J.M. Sc. 210: 765-774, December 1945.
22(1) King, R. B.: Spontaneous Rupture of Spleen in Infectious Mononucleosis; Report of a Case. New England J. Med. 224: 1058-1060, 19 June 1941. (2) Ziegler, E. E.: Infectious Mononucleosis; Report of a Fatal Case With Autopsy. Arch. Path. 37: 196-201, March 1944. (3) Darley, W., Black, W. C., Smith, C., and Good, F. A.: Spontaneous Splenic Rupture in Infectious Mononucleosis; A Case and Pathologic Report. Am. J.M. Sc. 208: 381-384, September 1944.
23Smith, E. B., and Custer, R. P.: Rupture of the Spleen in Infectious Mononucleosis; A Clinicopathologic Report of Seven Cases. Blood 1: 317-333, July 1946.
24See footnote 23.
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AGRANULOCYTOSIS
During 1942 and 1943, agranulocytosis was not separatelyindexed, and therefore data bearing on its incidence are not available. In 1944,a rate of only 1.0 per 100,000 troop strength was reported with a total of 8deaths. During the entire period of hostilities, only 37 accessions diagnosed asagranulocytosis were received by the Army Institute of Pathology. Althoughprecise figures were not available on how many soldiers received sulfonamidedrugs, it has been estimated that over 80 percent of the wounded were so treatedand often for considerable periods of time. The 15th Medical Hospital Center, inthe European theater, reported on 300 to 400 admitted casualties of whom 75percent received local sulfonamide and over 80 percent received oral sulfonamidemedication. This low incidence of agranulocytosis was therefore ratherremarkable. One explanation offered was that repeated examinations of blood weremade routinely on patients receiving sulfonamides in hospitals, and medicationwas stopped at the first indication of leukopenia.
NITROGEN MUSTARDS
Mustard gas, bis (?-chloroethyl) sulfide, which wasextensively employed as a poison gas in 1918 and which was known to have remoteeffects on hematopoietic tissues, was studied further after World War I. Itsadverse effect on leukopoietic tissues and on the growth of experimental tumorswas demonstrated. With the advent of World War II, biological research on gasesused in war was resumed and attention directed to the nitrogenous analogs ofmustard gas, the bis- and tris- (?-chloroethyl) amines, known as nitrogenmustards.
It was soon determined that these compounds owed theirbiological activity to their ability to undergo intramolecular cyclization in apolar solvent to form the highly reactive ethylenimonium cation.25This cation alkylates the functional groups of many compounds of biologicalimportance, and it is likely that the basic mechanism of the cytotoxic action ofthe mustards is through such a reaction with a vital cellular constituent.
In general, it may be stated that the susceptibility of cellsto the mustards is proportional to the proliferative activity of the cells.Thus, the blood-forming organs and the gastrointestinal mucosa are first andmost profoundly affected (as is also the case with irradiation, see p. 412).Following the intravenous administration of the nitrogen mustards toexperimental animals and to man, lymphocytopenia, granulocytopenia, andthrombocytopenia occur and, to a less extent, anemia. Marked effects on theblood may be obtained with doses of such a small size that nausea and vomit-
25Gilman, A., and Philips, F. S.: The Biological Actions and Therapeutic Applications of the ?-chloroethyl Amines and Sulfides. Science 103: 409-415, 5 Apr. 1946.
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ing are the only gastrointestinal effects. Larger doses leadto diarrhea which may become hemorrhagic. The outstanding pathological lesionsafter a mustard has been administered consist of (1) lymphatic fragmentation (asearly as 10 hours after injection), leading to atrophy of lymphatic structures,and (2) the early disappearance of all mitotic activity in the bone marrow,leading to depletion. With larger doses or prolonged administration, there wasalmost complete aplasia, and necrosis and desquamation of the gastrointestinalmucosa.
The marked effects of the mustards on lymphoid tissue coupledwith the finding that actively proliferating cells are selectively vulnerable tothe cytotoxic action of the mustards suggested the therapeutic use of thesecompounds in the treatment of neoplasms of lymphoid tissue. Because of itsundesirable physical properties and extreme chemical reactivity, sulfur mustardis not suitable for parenteral administration. However, nitrogen mustards in theform of their hydrochloride salts are water-soluble crystalline compounds thatcan be readily dissolved in sterile saline for intravenous administration.Experiments on transplanted lymphosarcoma in mice revealed that dissolution ofsuch tumors could be effected rapidly although the dose required bordered on thetoxic, and the tumor invariably returned.26 Thefirst clinical trial of the nitrogen mustards27was conducted on a group of six patients in the terminal stages of variousneoplastic diseases. In two cases of lymphosarcoma in which roentgenologictherapy had been discontinued, a rapid dissolution of large tumor massesfollowed a course of injections. The results were sufficiently encouraging towarrant further clinical experimentation. Since then, much clinical experiencewith nitrogen mustard has accumulated.
Although sporadic temporary remissions of symptoms, sometimesassociated with regression of primary or metastatic lesions, have occurred in avariety of malignancies-including some of neural origin-the onlystatistically significant results were observed in undifferentiated bronchogeniccarcinoma and in malignant lymphoma, particularly of the Hodgkin's type. Inbronchogenic carcinoma, striking remissions of fever, pain, weakness, cough, andanorexia have occurred. At times, these conditions were accompanied byregression of pulmonary infiltrations and of the signs of obstruction of thesuperior vena cava. In general, individual remissions were of relatively shortduration, measured in weeks rather than months, but often repeated courses oftreatment have continued to produce remissions (figs. 42 and 43).
In Hodgkin's disease, rapid improvement in the patient'sgeneral condition-disappearance of fever, gain in weight, and increase in thenumber of erythrocytes and hemoglobin-was accompanied by regression in the
26Dougherty, T., Gilman, A., Goodman, L., and Dougherty, J.: 1942-43. [Unpublished work cited by Gilman and Philips, see footnote 25, p. 406.]
27Gilman, A., Goodman, L., Lindskog, G. E., and Dougherty, J.: 1942-43. [Unpublished work cited by Gilman and Philips, see footnote 25, p. 406.]
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size of palpable lymph nodes, by reabsorption of pleural effusions, and bydramatic disappearance of enlarged mediastinal tumors. Figures 44, 45, 46, and47 show the roentgenographic appearance in a case of Hodgkin's granuloma and acase of lymphosarcoma before and after a course of treatment consisting of 0.1mg. per kilogram of body weight daily by intravenous injection on 4 consecutivedays. Remissions occurred more rapidly after therapy with mustard than followingirradiation, but these remissions seemed to be of shorter duration, althoughthis was not demonstrated in a large enough group to be of statisticalsignificance. The response to repeated courses of treatment appeared to be thesame as to the first course, although the duration might be longer, of similarlength, or shorter.
Patients who have had repeated courses of irradiation, andwho no longer obtain remissions from the largest dose of roentgen rays which theradiologist gives, might respond very well to the mustards and subsequentlyregain sensitivity to irradiation.
In contrasting mustard to roentgenologic therapy, it shouldbe pointed out that nausea and vomiting seem to be more frequent and severeafter the former and that leukopenia is less often seen after irradiation.
Mycosis fungoides responded in dramatic fashion to nitrogenmustard with relief of itching and involution of the skin lesions, leavingpigmented areas as the only clinically detectable residuum.
Although some remissions were observed in lymphosarcoma,mustard therapy has been disappointing in other types of lymphoma, both of thelymphoblastic and lymphocytic type. Acute leukemias and plasmoma (includingmyeloma) have not been benefited. Clinical results in both chronic myelogenicand lymphatic leukemia have not been satisfactory, although the peripheral bloodand the picture of the bone marrow may show improvement.
Results similar to those just presented were reported byother investigators.28
Although some patients receiving nitrogen mustards wereobserved for a period of several years, the evaluation of the clinical status ofthis group of compounds will require many more years of careful study. As yet,there is no basis for assuming that the therapeutic efficacy of the nitrogenmustards is any greater than that of irradiation.
28(1) Ap Thomas, M. I. R., and Cullumbine, H.: Nitrogen Mustards in Hodgkin's Disease; Report on 21 Cases and 4 of Other Reticuloses. Lancet 1: 899-901, 28 June 1947. (2) Goodman, L. S., Wintrobe, M. M., Dameshek, W., Good, M. J., Gilman, A., and McLennan, M. T.: Nitrogen Mustard Therapy. Use of Methyl Bis (?-chloroethyl) Amine Hydrochloride and Tris (?-chloroethyl) Amine Hydrochloride for Hodgkin's Disease, Lymphosarcoma, Leukemia and Certain Allied and Miscellaneous Disorders. J.A.M.A. 132: 126-132, 21 Sept. 1946. (3) Jacobson, L. O., Spurr, C. L., Barron, E. S. G., Smith, T., Lushbaugh, C., and Dick, G. F.: Nitrogen Mustard Therapy. Studies on the Effect of Methyl Bis (?-chloroethyl) Amine Hydrochloride on Neoplastic Disease and Allied Disorders of the Hemapoietic System. J.A.M.A. 132: 263-271, 5 Oct. 1946. (4) Osborne, E. D., Jordon, J. W., Hoak, F. C., and Pschierer, F. J.: Nitrogen Mustard Therapy in Cutaneous Blastomatous Disease. J.A.M.A. 135: 1123-1128, 27 Dec. 1947. (5) Philpott, O. S., Woodburne, A. R., and Waldriff, G. A.: Nitrogen Mustard in the Treatment of Mycosis Fungoides. J.A.M.A. 135: 631-633, 8 Nov. 1947. (6) Rhoads, C. P.: Nitrogen Mustards in the Treatment of Neoplastic Disease. J.A.M.A. 131: 656-658, 22 June 1946.
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ATOMIC BOMB AND APLASTIC ANEMIA
The medical complications of exposure to the atomic bombingof Hiroshima and Nagasaki were reported in part by the Joint Commission for theInvestigation of the Effect of the Atomic Bombs in Japan and abstracted byLeRoy.29
There were approximately 120,000 casualties in Hiroshima and65,000 in Nagasaki, about one-sixth of whom were either killed instantly or diedunder circumstances in which no medical care was possible. These people wereburned to death by the direct heat of the bomb, were crushed under demolishedbuildings, or were burned in the fires started by the bombing. It has beenestimated that about one-seventh of the total number of casualties escapedsignificant mechanical injuries or burns but received sufficient irradiation toproduce significant effects on the blood and blood-forming organs as well as onthe germinal epithelium and the intestinal epithelium. It appeared that theeffect of this extremely brief exposure (probably no longer than 1 second) wassimilar to that observed following massive roentgen irradiation of animals orthe administration of nitrogen mustard gas; that is, the destruction of tissuesin which active cell division occurred, such as the bone marrow, thegastrointestinal epithelium, and the germinal epithelium. In addition toionizing radiation, consisting principally of gamma rays harder than thoseproduced by any known electrical apparatus, alpha particles, beta particles, andneutrons were also produced, but the relation of these to the casualties is notclear. The intensity of the gamma radiation emitted by the bombs decreased asthe inverse square of the distance from the source of irradiation. It isaccordingly presumed that the most severe casualties were probably those closestto the center of detonation, although other factors, such as shelters, played arole.
Persons who were subjected to intense exposure and who werenot immediately killed or who did not die shortly thereafter of burns or otherinjury began to have nausea and vomiting within a few hours after exposure.Fever, diarrhea, and leukopenia began from the second to the seventh day.Purpura and thrombocytopenia generally did not appear until at least the fourthday. Death usually occurred in from 4 to 10 days. Examination of the blood insome cases was stated to have shown a total absence of leukocytes and platelets.Red urine was also reported. At necropsy, widespread ulcerative, necrotic, andhemorrhagic lesions were found in the gastrointestinal tract, together withdegeneration of all bone marrow elements. A photomicrograph of the spleen of a24-year-old man who died 5 days after exposure is shown in figure 48. This showsdisappearance of lymphocytes from the Malpighian corpuscles, cytolysis oflymphocytes, and fibrinoid changes in the subendothelial portion of the centralartery. Figure
29LeRoy, G. V.: The Medical Sequelae of the Atomic Bomb Explosion. J.A.M.A. 134: 1143-1148, 2 Aug. 1947.
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49 shows a section of the bone marrow of a 39-year-old manwho died 7 days after the bombing. It will be noted that few normoblasts remainand that there is proliferation of reticuloendothelium and of many plasma cellsand lymphocytes. These observations resemble those of Shouse, Warren, andWhipple30 in dogs receiving large,single doses of roentgen rays.
Individuals who received a less severe dose of irradiationhad early nausea and vomiting but then presented no symptoms for at least aweek, with the possible exception of diarrhea which occasionally began as earlyas 4 days after exposure. Leukopenia, anemia, and epilation generally begansometime between the end of the first week and the end of the first month;fever, thrombocytopenia with purpura, and ulceration of the mucous membrane ofthe mouth occurred in the third or fourth week; and anemia became manifest infrom 1 to 4 weeks after the detonation. Death occurred
30Shouse, S. S., Warren, S. L., and Whipple, G. H.: Aplasia of Marrow and Fatal Intoxication in Dogs Produced by Roentgen Radiation of All Bones. J. Exper. Med. 53: 421-445, 1931.
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in approximately 50 percent of the cases between 10 days and6 weeks after the bombing. Laryngitis, pharyngitis, tonsillitis, gingivitis, andtracheal and female genital ulcerations developed in many of these patients andpresented essentially the same appearance as that seen in malignant neutropeniafrom any cause. Petechiae and purpura appeared in the skin of almost all thepatients, together with epistaxis, melena, metrorrhagia and hematuria in many.The loss of hair was particularly marked in the scalp. Regrowth of hair did notbegin for several months in those patients who recovered. Leukocytes numberingas few as 100 cells per cubic millimeter were reported. Recovery was rare inthose whose leukocytes numbered less than 600 per cubic millimeter, essentiallyall of which were lymphocytes. Anemia was present in all such patients andbecame progressively more pronounced but did not occur until several weeks afterthe maximum leukopenia was observed. Presumably, the anemia was due, partly, tobleeding. In association with the leukopenia, serious infection and septicemiawere common. Apparently, the chief causes of death were pneumonia and infection.The
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bone marrow (fig. 50) of a 29-year-old man who died 29 daysafter the bombing shows marked hypoplasia, a necrotic area, and bacteria. Thecells were mostly reticulum cells, plasma cells, and lymphocytes. The spleen(fig. 51) of a 35-year-old woman who died 19 days after the bombing showsatrophy of the lymphoid tissues with karyolysis of some of the cells in thevicinity of the central arteriole. Hyalinlike material is deposited beneath thearteriolar endothelium.
Individuals with still less exposure may or may not havevomited on the day of bombing. They then were asymptomatic from 1 to 3 weeks.Diarrhea generally began from 2 to 5 weeks after the explosion as did epilation.Leukopenia was noted from the second to the fourth week, ulceration of themucous membrane in the third and fourth weeks, and anemia from the third tofifth week. Death occurred in the second or third month. It is uncertain whatproportion of these individuals succumbed, but those who died appeared to havean aplastic type of anemia. The hemorrhagic tendency in
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these patients was never severe, leukocytes numbering lessthan 1,500 cells per cubic millimeter were rare, and ulceration of the mucousmembrane tended to be transitory and not severe. Figure 52 is of the bone marrowof a 31-year-old man who died of bronchiectasis 14 weeks after the bombing. Thesection shows gelatinous marrow from the rib with a large focus of regeneratingcells replacing the fat.
LeRoy (p. 412) has summarized the important pathologicalchanges as follows: The bone marrow was badly damaged with an almost completedisappearance of all cells of the myelopoietic and erythropoietic series. In allbut the most severely irradiated patients, regeneration commenced within a weekto 10 days after injury. The type of regeneration of tissue varied considerably,and often the marrow appeared to be producing mainly macrophages, plasma cells,and lymphocytes 3 to 4 weeks after the injury with very few cells of thegranulocyte or erythrocyte series, although in
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other cases well-marked hyperplasia of these elementsoccurred. Tissue from patients dying early showed an almost complete absence oflymphocytes in the lymph nodes, the spleen, and the thymus. Recovery of thelymphatic elements was evident after a few weeks although, in many patients whodied several months after irradiation, the lymphatic tissues contained only afraction of the usual number of adult-type lymphocytes.
It seems probable that, had adequate measures been availableat Hiroshima and Nagasaki to combat serious infection by the use of antibioticsand to combat anemia with blood transfusions, the early death rate might havebeen considerably lessened. The evidence suggests that some of the very earlydeaths occurred from an overwhelming dose of gamma irradiation withoutconspicuous morphologic change at necropsy.
The sequence of events in those who survived this immediateeffect appears to be: First, a destruction of the marrow and lymphoid elements;then, following the destruction of marrow, the development of leukopenia
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and severe infection and the onset of thrombocytopenia andhemorrhagic phenomena; and finally, the development of anemia, with thedestruction of the circulating erythrocytes by normal processes. Thus, some ofthe early deaths resulted from leukopenia and sepsis before conspicuous bleedingoccurred. Others died with hemorrhagic manifestations (subarachnoid hemorrhagewas commonly reported in one group) after the onset of thrombocytopenia butbefore the development of anemia. Finally, late deaths were generally due toanemia associated with aplasia of the bone marrow.
A preliminary report was issued by Tullis andWarren31 onthe observations of animals exposed to the atomic detonation at Bikini. Theearliest lesions to appear were hemorrhages-involving almost any tissue of thebody and apparently associated with radiation injury-dilatation and congestionof the small blood vessels of the brain, heart, lungs, mesentery, bowel, andsubcutaneous tissue. Hemorrhages into the kidney, often filling the kidneypelves, were occasionally seen. The lymph nodes became extremely hemorrhagic;the lungs in 80 percent of the fatal cases were mottled, dark red, and pink. Thecut surface was wet and the bronchi were filled with abundant pink or whitefroth. The gastrointestinal tract showed ulcerative lesions of the largeintestine. The bone marrow sometimes was pale and sometimes hyperemic. Thelymphocytes in the peripheral blood were the first to fall, within a matter of afew hours. After a few days, the granulocytes decreased and at the end of from 1to 2 weeks the erythrocytes declined. Microscopic examinations were not yetavailable when this paper was written.
31Tullis, J. L., and Warren, S.: Gross Autopsy Observations in the Animals Exposed at Bikini. J.A.M.A. 134: 1155-1158, 2 Aug. 1947.
