non-reactive tuberculosis · in nowayabnormal, while that ofthe tuberculosis was usually rapid. in...

J. clin. Path. (1954), 7, 216.

NON-REACTIVE TUBERCULOSISBY

J. R. O'BRIENFrom the Portsmouth and Isle of Wight Pathological Service

(RECEIVED FOR PUBLICATION JANUARY 21, 1953)

Non-reactive tuberculosis has been reported undermany different names. It is called acute caseatingtuberculosis by Rich (1944), while on the Continentit is most commonly called Landouzyschekrankheitand the Yersin type of tuberculosis. It may bedefined as a fatal form of tuberculosis in whichmany organs contain miliary foci of necrosissurrounded by normal parenchymal cells. Typi-cally cellular response is completely absent, butoccasionally there is a poor response of the usualtype. Very large numbers of tubercle bacilli arefound in and around these lesions. Usually in lifethere are gross abnormalities of haemopoiesis, suchas anaemia or polycythaemia, agranulocytosis ora leukaenoid change, and thrombocytopenia.Rarely, the histological picture of non-reactivetuberculosis is found in leukaemia and myelo-sclerosis.

It is proposed to review the literature of non-reactive tuberculosis, to describe eight unpublishedcases, and to discuss the pathogenesis of this con-dition.

TABLE ISIXTY-SIX REPORTED CASES

Clinical Diagnosis No.

Asranulocytosis .. .. .. 22Leukaemod... 7Panmyelophthisis S

Polycythaemia .. .. .. .. 2Normal blood picture 6No record of blood 5Lalkaemia 13Myelosclerosis.5Hodgkin's disease 1

Total .. .. 66

There are sixty-six cases in the literature whichfulfil the criteria of non-reactive tuberculosis.Table I shows the number of cases subdividedaccording to various haematological changes. Apre-existing disease process may influence the courseof the tuberculous infection; accordingly, the 19cases with leukaemia, myelosclerosis, and Hodgkin'sdisease have been isolated in the table. Forty-sevencases remain in the main group.

Other cases are often quoted, but they will not beconsidered as they are unacceptable for the followingreasons: Weichmann (1922), R6th (1929), Holzer(case 2, 1927), and Reiche quoted by BAlint (1925)give no histological description. The cases ofReilly and Bolin (1931) and Loeschcke (1932) werenewborn infants and were probably cases of trans-placental infection.The salient features of the 47 cases in the main

group are summarized in Table II.

TABLE IISUMMARY OF CASES REVIEWED WITH NO INTER-

CURRENT DISEASE

*0

Group b

Males. 13 3 4 2 3 2 27No. Females .. .. .. 8 1 1 0 2 3 15

Total .22 7 5 2 6 5 47

Mean age .40 38 49 49 42 44 43

Duration f Less than 4 weeks . . 11 1 1 1 3 2 19of . ,,,,12 ,,.. 5 3 0 0 3 0 11

illness LMore ,,12 ,. . 2 2 4 1 0 110

Haemorrhagic incidents .. 5 3 2 1 0 0 11

fPresent 3.. 36 50 1 0 15Anaem1aY{Absent 8 1 0 0 0 0 9Necropsy:Old Primary Pesent 2 2 2 1 0 2 9MsOAsent .. 0 0 0Spl Enlarged 10 5 5 1 4 3 28Spleenl Normal .............. .. 2 0 0 0 0 0 2Liver narged 4 3 3 0 3 2 15Novrma~,l . . 4 0 2 1 0 0 7Nonaed-eyeabnormality . 3 0 0 0 1 0 4

Necrosis in marrow .. .. 9 1 2 0 1 0 13

TypeoffHuman .. .. 6 0 2 0 0 2 10bacillus_Bovine .. .. 2 0 0 0 2 0 4

In places in the table the number of cases in some of the sub-divisions does not add up to the total number of cases in the particulargroup. This is due to an absence of the relevant information insome of the papers.

Clinical Coum of Repored CasemThe commonest course seems to have been an

acute, overwhelming infection. Less often thesyndrome presented as a chronic pyrexia of

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NON-REACTIVE TUBERCULOSIS

unknown origin (Siegmund, 1939, case 6), some-times as an obscure anaemia, or apparently aspanmyelophthisis (Arends, 1950) or as primaryagranulocytosis. The terminal phase of the syn-drome may be complicated by tuberculous involve-ment of many organs. The skin sensitivity totuberculin was investigated only three times. Twiceit was weakly positive (Gibson, 1946; Arends, case 2,1950), and once negative (Hegler, 1938).

Post-mortem AppearanceIt is remarkable that the post-mortem examination

in four cases revealed splenomegaly, but no othermacroscopic change suggestive of tuberculosis. Inthe other 27 cases, in which lesions were described,they varied from pinhead size up to yellow areas ofnecrosis of 1 cm. in diameter. The spleen wasnearly always reported as enlarged, while the liverwas often enlarged. The glands often showed largenecrotic or caseous areas (Pagel and Woolf, 1949;Smith, case 1, etc., 1949), but more usually they werenormal. An old primary focus has been reportednine times, but several workers, particularly Sieg-mund (1939), have stressed its absence; he found no

primary in seven of the nine cases in which a reason-

ably thorough search appears to have been made fora primary lesion. Lastly, there are several reportsof tuberculous infection in a large number oforgans. There is one notable exception to thislist. No case of tuberculous meningitis has beenreported.

HistologyThe characteristic histological appearance was a

small area of necrosis, sometimes with the " ghost "parenchymal architecture still just visible. Appro-priately stained sections showed enormous numbersof acid-fast bacilli packed together forming felt-likemasses. Surrounding this area were normal paren-

chymal cells, but no inflammatory or other foreigncells. This lesion is described in the majority ofreports (for example, in the photomicrographs ofArends), but in quite a number of cases there was a

mild degree of lymphocytic or monocytic cuffing(Gibson, 1946). Gibson (1946), Holzer (1927), andothers have found evidence in some areas of a more

or less normal tissue response with a lymphocyticcuff, epithelial cells, and young fibre formation. Inall the cases accepted the atypical aspect of thebody response has been stressed or clearly described,but in some cases there was also a response inter-mediate in form between the typical non-reactivelesion and that in the normal tissue.The non-reactive lesions were always found in

the liver and spleen. They were almost always

present in the marrow. In the leukaemoid casesthe marrow was usually very cellular; indeed, inthese cases only the absence of leukaemic cellularinfiltration in the spleen and liver made possible theexclusion of a diagnosis of leukaemia. Otherreports (Marzullo and de Veer, 1931; Blair andPagel, 1947; Custer and Crocker, 1932) havedescribed a hypocellular and even fibrotic marrow.Commonly foci are found in the lungs and kidneys,but any organ, except, it seems, the meninges,may occasionally be similarly affected.

Bacteriology and MycologyCoincidental mycelial infection was reported in

four cases (Siegmund, case 3, 1939; Esser, 1926;Smith's cases 2 and 4, 1949). The type of tuberclebacillus was identified by adequate cultural methodsand animal inoculations in 14 cases. It was found tobe human in 10 cases and bovine in four.

Blood ChangesAgranulocytosis.-Of the 47 cases now under

discussion, 22 had leukopenia, or a total absenceof polymorphs (Leibowitz, 1938; Marzullo andde Veer, 1931; Smith, case 3). Anaemia was not afeature. Thrombocytopenia was present in the fewcases in which the platelets were counted, and wasalmost always associated with purpura. Wheninvestigated, the marrow was usually hypoplastic.Leukaemoid Count.-In the seven cases accepted

as having a leukaemoid blood picture, the total whitecount varied from 200,000 (Custer and Crocker, case1, 1932) to 4,000 (Gardner and Mettier, 1949; Leibo-witz, 1938; Staffurth and Spencer, 1950), but all hada high proportion of blast cells or myelocytes (Custerand Crocker, case 1, 1932) or prolymphocytes(Staffurth and Spencer, 1950) or even monoblasts(Gibson, 1946). Clinically, these patients survived onaverage a little longer than those with agranulocyto-sis, and they had splenomegaly and anaemia andhaemorrhagic incidents more frequently.Panmyelophthisis.-Four cases included are under

the heading of panmyelophthisis, all of which hadthrombocytopenia, granulopenia, and anaemia,which was extreme in two. Haemorrhagic incidentswere reported in two cases (Arends, case 1, 1950;Kemohan, 1950). Otherwise the clinical course inthese few cases did not differ from that of the wholegroup.Polycythaemia.-Two cases (Rennen, 1922;

Lederer, 1923) were thought clinically to havepolycythaemia. Both had over 7.5 m. red cellsper c.mm. and one (Rennen) had a high normalwhite count, with 90% polymorphs and an occa-sional nucleated red cell.

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Normal Blood Count.- In six cases the total whitecount was within normal limits, and the differentialcount when given was also normal. One of thesecases had previously been diagnosed as havingpernicious anaemia, but was having adequatetreatment at the time of his final illness (von Wyss,case 5, 1940).No Blood Count Reported.-Five cases are

included in which the blood was not investigated,but which are acceptable since an adequate his-tological description was given.Leukaemia.-In all the cases referred to so far

the diagnosis of leukaemia could be excluded withreasonable certainty. Thirteen cases, most of whichundoubtedly had leukaemia, will now be reviewed.A summary of the outstanding features in thecases of leukaemia, myelosclerosis, and Hodgkin'sdisease is presented in Table II1. When the

TABLE IIISUMMARY OF CASES REVIEWED WITH INTERCURRENT

DISEASE

Haematological Leuk- Myelo- Hodgkin's TotalGroup aemia sclerosis Disease

r Males .. .. 2 3 - 5No. Females .. .. 6 2 1 9

l Total .. 13 5 1 19

Duration r Less than 4 weeks 1 - 1 2Of ,, ,,12, 2 - - 2

illness More,, 12 4 5 - 9

Haemorrhagic incidents 3 1 0 4

Anaemia {Present 3 5 - 8

Necropsy:Old IPresent .. 4 1 - 5primary Absent I.I - - ISpleen Enlarged 7 5 0 12Normial .. 2 - 1 3Liver Enlarged 3 5 0 8

Normal . I - 1 2No naked-eye abnormality I - 0 1

Necrosis in marrow . - 3 1 4

Type of tubercle fHuman.. 3 - - 3bacillus 1Bovine 1 I

-

differential diagnosis between leukaemia and aleukaemoid change was in doubt, the cases havebeen included. Coley and Ewing's case (1911)probably had acute lymphatic leukaemia. Chronicmyeloid leukaemia was present in seven cases, whilelymphoblasts were found in one case (Fischer, 1935,case 1).The course of the leukaemia seems to have been

in no way abnormal, while that of the tuberculosiswas usually rapid. In four out of five cases inwhich there was relevant information, there wasevidence of old tuberculosis. The histologicalpicture of the non-reactive tuberculosis was typicalexcept that if there was any cellular response theceIl type was that of the leukaemia.

Myelosclerosis.-There are two reports of thishistological picture occurring in people dying withmyelosclerosis (Carpenter and Flory, 1941; Crail,Alt, and Nadler, 1940). In each case the myelo-sclerosis had been present for many months. Crailet al. report four cases associated with non-reactivetuberculosis and contrasts these with five other casesof idiopathic myelosclerosis. His tuberculouspatients were all comparatively young and all werefebrile; the duration of the illness was shorter thanthat in the idiopathic group. He suggests that inthese cases the tuberculosis first stimulates the fibro-sis of the marrow and the glands and subsequentdevelopment of splenomegaly and the leuko-erythro-blastic blood picture, with terminal haematogenousspread and the production of non-reactive lesions

Present SeriesCase 1.-H. B., a man aged 33, complained of bleeding

gums, a petechial rash, and haematuria. The onlyabnormal findings were some changes in the mid-zo.ie ofthe left lung in the radiograph of the chest, a plateletcount of 5,000 per c.mm., and a prolonged bleedingtime. He was given a pint of fresh blood and improvedclinically and the platelet count rose to 200,000 perc.mm. in 10 days. Forty-three days later he complainedof wasting, vomiting, abdominal pain, and loose stools.A radiograph of the chest and platelet count werenormal. The stools contained many acid-fast bacilli.The patient died 110 days after his original symptoms.The bacillus isolated from the stools was cultured byDr. A. Q. Wells and found to be a normal human typetubercle bacillus of high viiulence. Post-mortemexamination showed an emaciated man weighing 45 kg.Small miliary tubercles were visible in many organs.There was a small area of consolidation in the mid-zone of the left lung about 4 cm. in diameter. Theintestines showed gross tuberculous vlceration, while theportal glands were frankly caseous. The spleen (592 g.)was firm and had a finely granular appearance.The histological appearances are those of miliary

tuberculosis, but are remarkable for three reasons.There is necrosis rather than caseation. There are verymany tubercle bacilli within the epithelioid and giantcells and lying free in the tissues. Fibrosis is minimaland the cellular reaction consists chiefly of polymorphs,most of which are degenerate. Epithelioid systems arenot uncommon, but the cellular reaction generally ispoor. The lungs show tubercles of varying ages as wellas areas with necrosis with no tissue response. Thespleen is packed with miliary non-reactive tubercles.There are tubercles in many other organs.

This man succumbed to miliary tuberculosis andtuberculous enteritis with a histological picture verylike that of the non-reactive type nearly four months

L after an acute episode of thrombocytopenic purpura.The portal of entry was presumably the lung. Itshould be emphasized that the white cells were

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numerically and morphologically normal throughouthis illness.

Case 2.-F. I. N., a woman aged 59 years, began tolose weight and felt vaguely unwell 11 months beforeher death. These symptoms were slowly progressive.Pallor, fever, and an enlarged spleen were noted threemonths before her death. The haemoglobin was then58% (8.6 g.%). The white cells varied between 1,000and 2,500 per c.mm. while the differential count wasnormal and remained so throughout her illness. Theplatelet count was 70,000 per c.mm. Two sternal punc-tures showed marked hypocellularity with normal redand white cell maturation. The Westergren sedimenta-tion rate was 60 to 120 mm. in one hour. She wasgiven 3 pints of blood. The fever and wasting increased.The spleen enlarged to the brim of the pelvis. Shedied undiagnosed 11 months after the onset of symptoms,having pursued an apparently smooth course downhillwith increasingly rapid deterioration towards the end.

Permission was given for a partial necropsy only.The spleen had a normal cut surface. The liver andmesenteric glands appeared to be normal. Histologyof the liver and spleen showed vast numbers of tuberclebacilli matted into clumps, but the surrounding archi-tecture was not disorganized (Figs. 1 and 2). Clumps ofup to 15 bacilli could also be found inside normal livercells and others were lying free in the sinuses. Theabsence of any inflammatory response or fibrosis wasremarkable in both organs. Similar, but fewer, lesionswere found in the marrow.

There is no definite evidence to indicate when thenon-reactive tuberculous process began. Threemonths before death she had fever, splenomegaly,and granulopenia and the course of her illnessthroughout was a smooth one. Perhaps a chronictuberculous infection in some organ not examinedwas responsible for most of her illness, but it seemsmore likely that the whole course was associatedwith a non-reactive type of lesion.

Case 3.-E. E., aged 25, became ill four months afterhis wife died of pulmonary tuberculosis, when he com-plained of pain in the chest, a productive cough, andnight sweats. Seven weeks before his death a largepleural effusion was found. He became increasingly ill,breathless, and febrile. His sputum was repeatedlyexamined, but tubercle bacilli were seen only a few daysbefore his death. A culture of the sputum, taken threeweeks before death, grew M. tuberculosis. Three bloodinvestigations may be selected as typical of many (seeTable in next column).The report on the sternal puncture by Dr. J. C. White

emphasized the overwhelming white cell preponderance.Granulocytes at all stages of maturation were present,but some were morphologically abnormal. The fewred cell precursors were normal. He considered thisappearance compatible with subacute myeloid leukosisor leukaemoid reaction.At necropsy the liver, spleen, and lungs showed

numerous miliary tubercles. The lungs also showed

Days Before Death 43 5 1

Haemoglobin (%) 82 57Total white cells (perc.mm.) 32,000 82,000 15,000

Myeloblasts(2/0)25 1 1Promvelocytes(2)25 2 1Normal myelocytes (%0) 30 26 IMetamyelocytes (x0) - 14 11Stab forms(x0) 22 25 37Polymorphs (Y/,) 24 25 50Lymphocytes (°) 12 5 5 8Eosinophils (x0) - 1 -Mononuclears (%) 6-5 1 1Nucleated red cells per

100 white cells - - 4

nodules of caseous bronchopneumonia from 1 to 4 cm.in diameter. Some thoracic lymph nodes showed earlycaseation. The femoral marrow looked normal.

In the marrow there are a few scattered tubercles whichconsist of an area of necrosis containing a few epithelioidcells and nuclear remnants, but no giant cells. Thetubercles in the liver are typically non-reactive with nosurrounding tissue reaction whatever. No leukaemicdeposits are present (Fig. 3). The spleen is riddled withtubercles consisting of necrotic areas with much nucleardebris, a few lymphocytes and epithelioid cells and a veryfew spindle cells, probably fibroblasts. The lung showsmiliary lesions and massive confluent foci of acute nec-rosis. An occasional small collection of lymphocytesis the only cellular response. Sections, stained six yearsafter death by the Ziehl-Neelsen method, do not showany tubercle bacilli.

Infection probably occurred six months beforedeath and the lung was the probable seat of theprimary infection or reinfection. The clinical pic-ture was that of pulmonary tuberculosis and theleucocytosis was considered clinically in life to bea leukaemoid response to infection. Inspection ofFigs. 3 and4shows that the tissue reaction approachesto a slight degree that found normally. As thecausative organism was seen and cultured duringlife, it is curious that it cannot now be demonstratedin the sections.

Case 4.-M. R., a woman aged 54, gave a history ofthree years' illness with pulmonary tuberculosis, haemo-ptysis, and a pleural effusion which was repeatedlyaspirated. Two months before death she suddenlyexperienced severe upper abdominal pain, subsequentlyfound to be due to a large subcapsular haemorrhage inan infarcted area of the spleen. Examination revealeda large mass extending from the left ribs to the umbilicusand a just palpable liver. Repeated blood examinationshowed 6.7 m. red cells per c.mm.; haemoglobin,14.0 g.%; packed cell volume, 57%; platelets, 350,000per c.mm.; total white count, 30,000 per c.mm. (neutro-phil polymorphonuclear leucocytes 85%, lymphocytes12%, monocytes 3%). A very occasional myelocyteand nucleated red cell was also present. A sternalpuncture produced an almost acellular smear with adifferential count similar to that of the blood, but withthe addition ofabout 10% of polychromatic normoblasts.

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J. R. O'BRIEN

This examination could not be repeated. No treatmentwas given and the patient improved considerably.Three days before her death she had repeated severehaemoptyses. She was then febrile, cachectic, and dying.A fixed fluctuant swelling had appeared over the leftupper abdominal mass. A single blood examinationshowed haemoglobin 5.6 g.%, reticulocytes 6 per 100red cells, platelets 380,000 per c.mm., total white cells100,000 per c.mm. (neutrophil polymorphonuclearleucocytes 89%, lymphocytes 5%, polychromatic normo-blasts 6%, no myelocytes seen). At necropsy the lungswere seen to be riddled with extensive bronchopneumonicspread of tuberculosis through all lobes with marked oldcavitation and fibrosis. The small intestine containedtwo shallow ulcers extending horizontally round the gut,about three feet from its lower end. The spleen measured30 x 20 x 18 cm. with a large fluctuant subcapsularhaematoma overlying an irregular wedge-shaped infarct.No tubercles are seen in the liver or spleen. The

spleen, and to a lesser extent the liver, is heavily infiltratedwith polymorphs, but no necrotic foci are present. Amesenteric gland shows typical normal tuberculouscaseation. The marrow from several places showsincreased cellularity with a preponderance of granulo-cytes. There is neither sclerosis nor fibrosis nor is thepicture that of leukaemia. In none of the organsdescribed so far were acid-fast bacilli demonstrated.The lungs everywhere showed gross disorganization

with much caseation and fibrosis and a scanty cellularresponse of the normal type. In contrast, but oftenadjacent, were areas of necrosis full of nucleardebris with no surrounding cellular reaction, whichcontained very many acid-fast bacilli. Adjacent to oneof these areas was a small blood vessel containing redcells and polymorphonuclear leucocytes. There were anumber of acid-fast bacilli free in the lumen of the vesseland inside polymorphonuclear leucocytes.

Sections through the ulcers in the small intestineshowed in some areas the normal tissue response to theinfection and contained no acid-fast bacilli. Adjacentto these areas were a few quite different lesions withintense polymorphonuclear leucocytic infiltration, nucleardebris, and a few lymphocytes, giving the appearance oftiny abscesses. There were very many acid-fast bacilliin almost all these areas. Adjacent were a lymph vesseland a blood vessel, the latter partly occluded by acellular thrombus, both of which contained considerablenumbers of intravascular acid-fast bacilli.

This patient had chronic pulmonary tuberculosis,and for at least two months she also had grosssplenomegaly and a high red and white cell count.These findings cannot be explained by any ordinaryhaematological diagnosis and it is remarkable thatthe picture should have been associated withhistological evidence at death of non-reactive tuber-culosis in some organs. After years of a normalresponse to a tuberculous infection which wasslowly advancing, the body's defences were suddenlyoverwhelmed, but in an unusual fashion.

The following four cases, very kindly given tome by Dr. F. B. Smith, were presented by him tothe Association of Clinical Pathologists in 1949,but have not been previously published.

Smith: Case 1.-A man, aged 59, was admitted withgeneralized purpura and clinically was suspected ofhaving typhoid fever. Clinical details are now lacking.His illness lasted for about one month. The totalwhite cells numbered 3,000 per c.mm., but there was norecord of the differential count.At necropsy there was a thick exudate on the fauces

and pharyngeal wall suggesting agranulocytosis. Thepleural cavities were obliterated by old fibrous adhesions.The lungs appeared normal. The liver was slightlyenlarged and contained sparse, ill-defined, small, paleyellow foci. The spleen was not enlarged and containeda few similar foci. The mesenteric glands were soft andmatted together and contained fine miliary foci suggestingan acute tuberculous process.The small foci in the liver, spleen, and portal glands

showed necrosis with a complete absence of surroundingtissue response. They were packed with large numbersof acid-fast bacilli resembling M. tuberculosis.

This case appears to be a good example of acutetypho-tuberculosis as it is described in the Germanliterature.

Smith: Case 2.-A man, aged 52, became ill onemonth before his death. One week before death hewas in a drowsy typhoid state with an intermittent rash,bleeding gums, and purpura. Repeated blood examina-tion showed a haemoglobin of 75%, a total white countfrom 1,000 to 3,200 per c.mm. with only 500 to 800polymorphs per c.mm. His condition steadily deterior-ated until his death.At necropsy an old scar from an empyema drainage

wound was noted. The pharynx and fauces wereextensively ulcerated. There were old fibrous adhesionsin the right pleural cavity. The lungs contained smallhaemorrhagic foci. The liver (1,700 g.) and spleen(420 g.) contained small and inconspicuous pale yellowfoci. A few small ulcers were present in the duodenalmucosa. A single tracheal gland was moderatelyenlarged. The marrow in the femur was essentiallynormal.The liver, spleen, gland, and marrow showed miliary

areas of necrosis with no tissue reaction containing acid-fast bacilli, occasionally in very large numbers. In themarrow bacilli were seen both in the necrotic areas andlying free among the normal marrow cells. There weresome miliary necrotic foci in the lungs, which containedno acid-fast bacilli. Sections of these areas and of theduodenum were examined by Dr. J. T. Duncan, whoconfirmed the presence of mycelia and spores, andconsidered, in the absence of culture confirmation, thatboth sites were probably infected with monilia and thatthe lungs were infected with aspergillus as well.

Smith: Case 3.-A spinster, aged 65, four monthsbefore death had a macrocytic anaemia with a haemo-globin of 56%, and histamine-fast achlorhydria. The

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total white cell count was constantly about 1,000 perc.mm. until her death and there were usuall only 100polymorphs per c.mm. while almost all the other cellswere lymphocytes. There was no response to intensiveliver therapy. A sternal puncture showed hypoplasiaof the marrow with a gross preponderance of immaturegranulocytes. She was transfused, but relapsed. Shewas transfused again and the haemoglobin remained at80% until death. One month before death she becamefebrile for the first time and irrational. She died after aslowly progressive illness lasting 10 months.

Necropsy showed a liver of normal size and a slightlyenlarged spleen with, in both organs, scanty, incon-spicuous miliary foci similar to those seen in the last twocases. Sections of the liver, spleen, and tracheal glandsshowed miliary, and occasionally confluent, areas ofnecrosis. These areas contained nuclear remnants, butwith no surrounding cellular reaction. Large numbersof acid-fast bacilli were seen in all three sites.

This patient, with a 10 months' history, againraises the question of when she was infected withthe tubercle bacillus. Was it a month before herdeath when she became febrile, or had she beeninfected from the beginning ?

Smith: Case 4.-W. M. J., a man aged 45, hadpleurisy as a young man. Five months before his deathhe apparently had pneumonia, with a haemoptysis andlater a small hydrothorax. He had intermittent fever,recurrent, severe, staphylococcal abscesses, and wentslowly downhill. Blood examination showed a haemo-globin of 55 to 65%; the total white cell count variedfrom 2,000 to 4,000 per c.mm. with 14 to 28% eosino-phils. Sternal puncture showed hypoplasia of thegranulocytic series. M. tuberculosis was not isolated inlife. Post-mortem material was sent to Dr. A. Q.Wells, who grew and identified normal M. tuiberculosisof human type. Monilia was repeatedly found in thesputum and mycelia were also present. These wereidentified culturally from post-mortem material byDr. J. T. Duncan as Aspergillus fumigatus.At necropsy the lungs showed a few small firm yellow

nodules which contained the mycelia of aspergillus, butno tubercle bacilli. The spleen (430 g.) was dotted withwhite foci up to 3 mm. in diameter. The tracheal andpara-aortic glands were enlarged and firm. Sections ofthe spleen and glands showed the characteristic areas ofnon-reactive tuberculosis. Large numbers of tuberclebacilli were present in these sites.

Entry was presumably by the lungs. The clinicalcourse was conspicuous for the frequency andseverity of the pyogenic infections. Both this andthe mycelial infection were presumably due to thelowered resistance of the patient associated withthe leucopenia. The evidence is not sufficient toprove whether the tuberculosis or the agranulocyto-sis came first. The fact that his first complaint waspneumonia and haemoptysis suggests that pulmonarytuberculosis was the first lesion.

DiscussionAre there sufficient common trends in the cases

reviewed and reported to justify the concept of asingle disease process ? Undoubtedly the tuberclebacillus is common to all, but the variation in thereaction of the host is considerable. No caseshave been included that had a normal tissueresponse to tubercle, but many cases have somefeatures of the normal reaction, at any rate in someof the lesions. It seems probable that there arecases in which the tissue reaction is intermediatebetween the normal and the non-reactive types andthat the cases under discussion merely represent anextreme degree of one type of tissue response.

The Parasite.-From the time when this conditionwas first recognized until recently there have beensuggestions (Yersin, 1888; Loewenstein, 1934) thatthe causative organism was an avian type of tuberclebacillus. In no case has there been conclusiveexperimental proof of this assertion, and there arenow many reports in which the causal organismswere proved to be a tubercle bacillus of the normalhuman or bovine types.

The Host.-There is considerable evidence thatthe tubercle bacillus is not immediately harmful tothe normal living mammalian cell. For example,in tissue culture experiments Brieger (1949) grewexplants of uninfected animals and found that whenthese explants were infected with tubercle bacillisome of the bacilli were " phagocytosed and con-tained in the macrophages for long periods with allthe signs of a perfect symbiosis." It also seemsthat no extract from the tubercle bacillus is lethal oreven toxic when injected into the living uninfectedanimal as a single dose. It must be assumed,therefore, that the tubercle bacillus does not nor-mally kill by the manufacture of a cellular poison.When bacilli grow in the body they liberate productsof metabolism that are treated as foreign proteinsby the body. It is the nature of the sensitivityresponse of the body as a whole that largely deter-mines the nature of the local tissue response to thelocal liberation of an essentially bland foreignprotein. The fate of the patient now dependschiefly on the balance struck between the localtissue defence and the response of the body as awhole to the products of the bacillus, i.e., itssensitivity.

Bloch (1950) infected animals with three-day-oldcultures of bacilli containing a high cord-factor con-tent. Fifty per cent. of these animals died in 14 dayscompared with a 50% survival rate for 32 days inidentical animals injected with three-week-oldcultures. These results may be explained in a

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manner differing from that put forward by Blochhimself. The three-day-old cultures are presumablygrowing logarithmically and producing from themoment they are injected large quantities of meta-bolic products. Normally the infecting dose iscomparatively small, growth of the bacilli certainlyis initially slow, and therefore the intensity andduration of the antigenic stimulus is different. Itmay be the timrre factors and the quantity but notthe quality of the tuberculous products that producedthe abnormal response in Bloch's mice.

In a normal person infected with tubercle thereare few bacilli in the tissues and a vigorous localtissue response. One must assume that the sensi-tivity induced is the right kind to produce thevigorous local response. In non-reactive tuber-culosis there are very large numbers of bacilli andno tissue response and therefore it seems veryprobable that the nature of the induced sensitivityis different.The suggestion is therefore put forward that in

human non-reactive tuberculosis it is the rate ofliberation, or the quantity of the products ofmetabolism of the tubercle bacillus, that evoke astate of abnormal sensitivity in the patient. Alter-natively or additionally, it is suggested that thesepeople are in an abnormal state and cannot producea normal sensitivity response.An almost identical histological lesion occurs in

voles (Wells and Robb Smith, 1946) infectednaturally with the murine type of M. tuberculosisin an illness which, incidentally, may last severalmonths. Similar appearances are also found inrats and mice infected intravenously.The histological appearances of the lesions in

transplacentally infected human babies are oftensimilar. Two features of this infection seem todifferentiate it from adult primary infection. First,the infection is blood-borne from the start and thedose is probably heavy, and secondly, and probablymore significantly, the mechanism for the productionof antibodies is imperfect in the neonatal period.-.

In some patients treated with cortisone for somequite different disease an unsuspected tuberculouslesion has advanced rapidly. The histology of theselesions is strikingly like that found in naturallyoccurring non-reactive tuberculosis. It appearsthat the probable explanation in these patients isthat the mesenchyme cannot proliferate and differen-tiate in response to an appropriate stimulus. Thehistological appearance may in any case be attri-buted to paralysis of the primitive mesenchymalcell, and this explanation is supported by theobservations that other stimuli of widely differingcharacter cannot stimulate a response of the mesen-

chyme in animals treated with cortisone (Sissonsand Hadfield, 1951).The association of non-reactive tuberculosis with

true leukaemia, which is usually chronic, is sofrequent relative to the total number of reportedcases of non-reactive tuberculosis that it cannot beexplained by chance. In these cases it must beassumed that the leukaemia develops first andpredisposes to this type of tissue response if thesubject becomes infected with tubercle. Siegmund(1939) maintains that this type of lesion canoccur only in a primary infection or in a secondprimary infection when the patient has antigenicallycompletely recovered. Reference to Tables II, III,and the case reports show that in at least eight casesin the non-leukaemic groups and in all five of theleukaemic cases there was good evidence of an oldactive tuberculous infection.Duration.-The histological appearance of non-

reactive tuberculosis suggests an acute process, butmany of the patients dying with non-reactive tuber-culosis have been ill for months. It has alreadybeen mentioned that voles may survive with thishistological picture for some months before theysuccumb. Clearly in most cases the non-reactivenature of the tuberculous lesion will only be estab-lished at death and so its duration must be sur-mised. The indirect evidence suggests that it mayexist in man for some months.

Abnormalities of the Blood.-All but five of thereported cases of non-reactive tuberculosis in whicha count was carried out had some disproportion ofhaematopoiesis. Arends (1950) has claimed thatthe common factor in non-reactive tuberculosisis an abnormality of the blood, and that thispredisposed to an abnormal tissue response.The occurrence of this type of lesion in leukaemia,and possibly in myelosclerosis and Hodgkin'sdisease, in which the polymorphs are known to beabnormal, is then easily explained. There are,however, cases of non-reactive tuberculosis inwhich the polymorphs and all the other types ofcell have remained normal throughout the courseof the illness. Blood changes vary considerablyand are most unlikely to be the cause of the abnormaltissue reaction, although this possibility cannot beexcluded. There are, therefore, two possibilities.They may be brought about by the mechanicalpresence of the bacilli and the areas of necrosis inthe marrow, but examination of the marrow showsthat a very high proportion of the total volume ofmarrow is still histologically normal, so this explana-tion seems unlikely. The second possibility is adirect action of the products of metabolism of thetubercle bacillus on the marrow. It is now suggested

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that the marrow cells are in a state of abnormalsensitivity, in a manner somewhat similar to theabnormal state already postulated for the cells ofthe other organs, and that it is this abnormalsensitivity of the body that explains the coincidenceof non-reactive tissue response and the abnormalblood picture.Aronson (1931) showed that tuberculin has a

specific cytotoxic action on tissue cultures of themarrow and other tissues from infected animalsand that the same small dose of tuberculin wasinnocuous to tissues from healthy animals. Thiswork was largely confirmed by Moen and Swift(1936). Sensitivity of this type might explain thecases of agranulocytosis. Feldman and Stasney(1937) established experimentally that under certainconditions the products of metabolism of tuberclebacilli stimulated granulocytosis and produced aleukaemoid blood picture. The difference betweenstimulation and inhibition, particularly in this fieldof sensitivity, is probably slight, and the paradoxof agranulocytosis and leukaemoid changes occur-ring in the same disease process may not be soimprobable as first appeared.

This suggestive ambivalence of the reaction ofthe marrow to the products of tubercle bacilli findssome support in the work of Smith (1951) on themeninges. When she injected tuberculin intrathe-cally in cases of tuberculous meningitis, usually aviolent cellular reaction with an outpouring ofpolymorphonuclear leucocytes was produced. Inthose patients who were Mantoux-negative noresponse was obtained.

SummaryNon-reactive tuberculosis is defned as a his-

tological condition in which there are miliary areasof necrosis containing large numbers of tuberclebacilli surrounded by normal parenchymal cells ora minimal degree of the usual tissue response.There are 66 acceptable reports of this condition inthe literature which is reviewed. The clinical courseof the disease is most varied. It may be that of arapidly overwhelming, typhoid-like illness or it mayapparently continue for many months.

Its association with an abnormal blood pictureis striking. Agranulocytosis, obscure anaemias,leukaemoid changes, and thrombocytopenia arefrequent, and the condition is also found in patientswith chronic leukaemia.

Eight previously unpublished cases are reported.The mechanism of the abnormal tissue response

and its association with an abnormal marrowresponse is discussed in the light of recent experi-mental work.

For permission to publish these cases I have to thankthose doctors under whom they were admitted, namely,Professor L. J. Witts for Case 1, Dr. G. R. Steed andDr. S. Noy Scott for Case 2, Dr. Nellan and Dr. J. C.White for Case 3, and Dr. W. A. Lister and Mr. G. L.Preston for Case 4.

I am also most grateful to Dr. F. B. Smith for per-mission to publish for the first time the four cases hepresented to the Association of Clinical Pathologists in1949; one of these, Smith Case 4, was actually investi-gated by Dr. H. G. Close, to whom I am also indebted.I also have to thank Professor T. F. Hewer's Departmentof Pathology for the photomicrographs.

I also am glad to acknowledge the kindness and helpof Dr. E. M. Brieger, Professor G. Hadfield, ProfessorT. F. Hewer, Dr. R. G. MacFarlane, Professor DorothyRuissell, and Dr. A. Q. Wells.

AddendumSince this paper was prepared, Friend and

Thackerary (1952) have reported four cases of theassociation of tuberculosis and hepatosplenomegalywith an abnormal blood count. One case hadtypical non-reactive lesions. It has not beenincluded in the tables.

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359.Esser, A. (1926). Beitr. Klin. Tuberk., 63, 699.Feldman, W. H., and Stasney, J. (1937). Amer. J. med. Sci., 193, 28.Fischer, W. (1935). Beitr. Klin. Tuberk., 87, 334.Gardner, F. H., and Mettier, S. R. (1949). Blood, 4, 767.Gibson, A. (1946). J. Path. Bact., 58, 469.Hegler, 0. (1938). Dtsch. Arch. klin. Med., 183, 1.Holzer, K. (1927). Beitr. Klin. Tuberk., 66, 245.Kernohan, R. J. (1950). Brit. med. J., 2, 399.Lederer, K. (1923). JVien. Arch. inn. Med., 5, 23.Leibowitz, S. (1938). Arch. Path., Chicago, 25, 365.Loeschcke, H. (1932). Beitr. Klin. Tuberk., 81, 171.Loewenstein, E. (1934). Schweiz. med. Wschr., 64, 808.Marzullo, E. R., and Veer, J. A. de (1931). Amer. J. med. Sci., 182,

372.Moen, J. K., and Swift, H. F. (1936). J. exp. Med., 64, 339.Pagel, W., and Walf, A. L. (1949). Amer. Rev. Tuberc., 59, 311.Reilly, W. A., and Bolin, Z. E. (1931). Amer. J. Dis. Child., 41. 582Rennen, K. (1922). Beitr. Klin. Tuberk., 53, 197.Rich, A. R. (1944). The Pathogenesis of Tuberculosis. Thomas,

Springfield, Illinois.Roth, N. (1929). Beitr. Klin. Tuberk., 71, 634.Siegmund, H. (1939). Beitr. path. Anat., 103, 431.Sissons, H. A., and Hadfield, G. J. (1951). Demonstration: Inter-

national Congress of Clinical Pathologists, London.Smith, F. B. (1949). Presidential Address to Association of Clinical

Pathologists, England.Smith, H. (1951). Personal communication.Staffurth, J. S., and Spencer, H. (1950). Blood, 5, 1161.Wells, A. Q., and Robb-Smith, A. H. T. (1946). Spec. Rep. Ser.

med. Res. Coun., Lond., No. 259. H.M.S.O., London.Wiechmann, E. (1922). Med. Klin., 18, 1086.Wyss, W. H. von (1940). Helv. med. Acta, 7. 430.Yersin, A. (1888). Ann. Inst. Pasteur, 2, 245.

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