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The

Pathogenesis
CHARLES

of

Tuberculosis
M.D.*

M. NICE, JR., Minneapolis, Minnesota

Introduction There ogenesis more cognize of opinion factors different quate are many unanswered of tuberculosis. However, complicated many in modifying conditions control events regard the and observations.
Some Basic Terms

questions this occur

concerning complex subject terminology, failure of to any recognize

the is

pathmade to rethe under ade-

by

lack that to their In

of may

uniform origin, different

regardless failure of localities, tuberculous

difference fully

development

disease and lack of

Recognition discussion. where the


complex

of

the

terms

to

be

employed

is

paramount

in

any

A primary first infection includes vessels the and direct

focus is the lesion produced with tubercie bacilli occurs. primary nodes. or focus and A progressive contiguous a period refers to dormant the
primary

in any tissue The primary


lesion

involved of disease

lymphatic which

efferent is one from inaca disof

results

from

extension

a primary focus, tivity. Endogenous ease locus that time. Exogenous out which occurs infection. external culous lesions body, a caseous entirely tuberculoma center replaced source lesion. uniformly and implies is an

with or without exacerbation has remained reinfection in an which is

of comparative a reactivation for a variable infection a healed of infection an or size in This the in the
Miliary

of period

indicates individual
(if

a new who has consists upon refers an of organ

from withtuberculous from tuberthe A contains may be or brain It may extension of progresa
endobron-

Superin/ection Miliary

It exists)

an

superimposed through lesion to

unhealed throughout of which lesion liver lung infection.

tuberculosis distributed a hematogenous isolated tends fibrous

to numerous

millet-sized

dissemination variable

and by

be encapsulated. tissue. it is seen but foci). by

as a result result from chial through the hematogenous *From versity

of hematogenous bronchogenic are bronchi, spread. small

dissemination, spread (round lesions initiated and lack Phthisis

metastases

secondary

the homogenous distribution indicates a wasting or Physical Hospitals,

the Department of Minnesota,

of Radiology and and the University 550

Therapy of the UniMinneapolis, Minn.

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Vol.

XVII

THE

PATHOGENESIS

OF

TUBERCULOSIS

551 and Is usually

sive used

disease, In

more

or less with

limited lung Portals

to an disease. of

organ

system,

connection

En try-3 of milk Is extensively pracwell over via the gastroof One a later entry Transportal portal

In

countries

where of the The the example another

pasteurization entry cases. skin and placenta the tissue tonsil, such Modes as of be is via the Occasionally focus has been at is rare, may the rarely in

ticed the portal 90 per cent of oral intestinal in of of ritual entry, entry mission cavity with tract.

respiratory there the other but not lung. tonsil mentioned sites is

tract in is infection or as of reported. in trauma. the a portal

a primary

circumcision through for in

preclude

Spread2 propagated by vein), by intestinal Infection entrance


primary focus

Tuberculous via (e.g., tree bronchi lymphatics thoracic (bronchogenic to trachea

infection or duct blood to left

may stream,

by

contiguous the tract).

spread, spread bronchial (e.g., spread

lymph-hematogenous through intracanalicular

subclavian or to of gastro Tuberculous of


The in

spread), to larynx Pattern is


for be

Basic The
Into the the lungs

individual
body may

unaware
time:

the lobe,

of

tubercle
of Infection

bacilli
in

some located

any to

usually

subpleurally.

After

an focus

weeks),

incubation the or

period tuberculin Levine4

of

three reaction may 16

eight weeks (average can be elicited and or may not who be visible had children

four to six the primary upon x-ray demon-

primary by

complex found most

examination. strable reaction.

lesions be

roentgenogram However, In

before cases

the development the reverse may

of tuberculin true. Usually

the roentgen 10 to 16 weeks tion may be initial include invasion fever,

signs, when present, may be after infection occurs. Indeed, the only indication of infection, may malaise, be accompanied anorexia, by symptoms weight

demonstrated within the tuberculin reacor the period of and cough, signs. These wheezing,

loss,

increased erythrocyte sedimentation rate, neutrophilic leukocytosis followed by monocytosis or lymphocytosis, phlyctenular conj unctivitis and erythema nodosum. The last-mentioned is quite common in the Scandinavian countries, but is uncommon In the United by facfactors, In It the
Wall-

States. The subsequent course of events may be modified tors of indIvidual resistance, age, sex, race, soclo-economic
etc.2 ages

The
of

period
birth to

of
three

Initial
years

Invasion
and from

is second

especially
15 to 35

dangerous
years, which

gren

designates

as

the

first

and

danger

periods.1

Is like-

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552 wise dangerous to be influenced in Minnesota During are the in than stage spread. disseminated the by in of

CHARLES

M.

NICE,

JR.

May,

1950

Negro and geographic the

in some variations

social

groups, (e.g., less usually cases blood the

and seems dangerous a first

Scandinavian Initial invasion this Is meant the reaction the Koch throughout

countries). there is that body in most by

hematogenous bacilli probably lesions

By

tubercle stream,

before6 the tuberculin tend to be localized by generalized result at at to to six a later months this

is in evidence. phenomenon miliary foci may longer) by fibrosis,

Subsequent when allergy tuberculosis tend to heal the completed may not initial the show hand,

develops. However, or meningitis may only After complex and/or triad evidence the primary period to phthlsis,9 tissue develop invasion tion of to reactivate four tends

hematogenous time, or the (but sometimes to yet heal may fully

date. and calcification

stabilize,

resolution.7 depicted In of disease

The patient figure 1, and on the

thus have 75 per cent On the

roentgenogram.

other

lesion may proceed directly or a more advanced disease process,8 with extensive Involvement of the and and

after a variable latent or even to a wasting contiguous pulmonary pneumonia compression including These consist latter may or formaconto designate of caseous in a few nodule within only

(figure 2). Also, a non-caseating in the surrounding area, may cyst-like lead to blebs obstructive or bullae,

or serous bronchial

emphysema,#{176} atelectasis. as epituberculosis picture did not tissue, and could a small fibrous may result however, is usually

ditions were previously designated that the entire roentgenographic or tuberculous months, leaving as evidence In a high Since 9 to percentage the primary inflammatory at times This of cases, only

resolve or calcific resolve

of disease.

atelectasis

in bronchiectasis

if it doesnt located

12 months.11 lesion subpleurally,

Fi rsf Hemalogenous Dissemination

Involvement Focus
FIGURE 1: Basic

-+0

Lymph eqiona Nodes


of Infection.

Pattern

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Vol.

XVII

THE

PATHOGENESIS

OF

TUBERCULOSIS the result. controlled, may lead or multiple metastases. advanced this progression hematogenous other unhealed It may
the three

553 surface, an to results endogenous bronchogenic in the suband

minimal pneumothorax If the exacerbation dissemination


clavicular

extension or primary or of
minimal

is pleural lesion exogenous disease.

required effusion

to

reach may be

pleural

appears to reinfection This quite single

commonly

infiltrate,

tuberculomata Apico-caudad or even the organ far bacilli dismay lesions, is included result exacerbation,
plus the

(round extension advanced may enter semination, reactivate,

foci) may

or

miliary endobronchial then produce moderately At blood any stream time during for

lesions. the

a secondary

or a small focus of disease in some progress and invade the blood stream. occurring but
or

Superinfection, may be a factor, completeness.


phthisis

in still
of

the awaits
the

presence definite
lung

of

this
wasting

proof. tissue

only for Thus, the


exogenous

from

progression

of
reinfection,

the

primary
or from

lesion,
any one

endogenous
of

possible superinfection, host resistance is


in organs or systems

if disturbed.
other

the
than

balance of bacillary virulence This progressive disease may


the lungs. At any stage of

and occur
disease

in to

any invade

organ the

a lesion blood

may stream. to Involved

progress

to

produce

local

phthlsis

or

What We primary

Happens

Regional the may

Nodes?

(figure

3) of proceed the to

have already focus. The

discussed nodal lesions

various consequences likewise heal or

FIGURE

2: What

Happens

to the

Primary

Focus?

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554 caseation. to route pression physema result death. positive to


the

CHARLES

M. NICE,

JR.

May,

1950

The sputum,

caseous and
and larynx

node the

may bacilli

perforate may take

a bronchus,2 the
tract.

leading
com-

intracanalicular
Bronchial

gastro-intestinal

or invasion or atelectasis. in a complete The caseous then

leads

to manifestations Discharge of a large blockage of the rima may perforate to the Rupture tuberculous and the subclavian of caseous pericarditis. leading atelectasis,

of obstructive emcaseous mass may glottis with sudden thoracic duct and initiate into difficulties may in turn the a the hilar vein to material Calcified to future which

node

bacilli are hematogenous pericardlum nodes such lead may

conducted dissemination. cause pneumonias

may produce

bronchostenosis,3

as recurrent to bronchiectasis. What Happens 4 the are tissue,

to progressive

the

Progressive primary it may

Primary lesion heal, tree, and spread or

Lesion? its invade subsequent through the the blood

In

figure

possibilities surrounding stream. What

shown. involve

Briefly, the

bronchial

Happens

to bacilluria

the

First may

Hematogenous be the This and only

Spread? demonstrable

(figure

5)

A transient of of the any

evidence

first hematogenous other urinary bacilli go through Hematogenous

spread. findings, the millary

may occur in the absence some even believe that the or This is difficult meningitis may

tubercle to prove.

intact glomerulus. tuberculosis

Involved Regional Nodes

FIGURE

3: What

Happens

to Involved

Regional

Nodes?

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Vol.

XVII

THE More reactivate often after

PATHOGENESIS the disseminated a period of

OF

TUBERCULOSIS

555 quiescent, years, but givIng hean while system less fre-

occur. may

foci remain few months to nothing the

or

rise to progressive matogenous spread. active or lesion, an a progressive

organ Thus, apparently

disease and at times a chest roentgenogram healed lesion is starts lesion, present in the or in

a secondary may reveal at skeletal all,

tuberculous frequently

kidney. Bone tuberculosis

metaphysis,

Progressive Primary Lesion

FIGURE

4: Consequences

of First

Hematogenous

Dissemination.

Tuberculoma

of

brain

Paraverfebr& abscess

I
Tuberculous

I LffusIon
Pleural

meningihs

FIGURE

5:

What

Happens

to Progressive

Primary

Lesions?

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556 quently in the epiphysis.

CHARLES

M.

NICE,

JR.

May.

1950

The

lesions Poncets may presence

may

penetrate in the

the

joints,

slowly destroying gic type of joint weeks, joint the


lesions

the cartilage.4 swelling which not and Indicate cyst-like the and the phalanges

rheumatism disappear of appear (spina bone tubercle in ventosa),

is an allertwo to three bacilli diaphyses simulating of this thus form. the may be reLarge in the of

and space. long seen is to the the the

does bones in

Rarely, sarcold

lesions

coccidoidomycosis. type of paravertebral of

Tuberculosis tuberculosis; abscess, and or pleural may

spine lead sponsible In areas block, space2 In heal


spreads by

most frequent formation of the development solitary

for brain

meningitis tuberculomata

effusion.

or multiple

of involvement and cortical to the and produce bacilli) liver, calcify


Inward

in the mid-brain lesions may rupture meningitis. or and form


the spread

may lead into the may be demonstrable or multiple

to ventricular subarachnoid (with bacilli). may


and salpingltis

Meningitis serous kidneys progressive


cortex downward. to

bacillary foci
pelvis

demonstrable

(without single
the

spleen or
from

either
thence may

lesions.
renal Tuberculous

Renal

tuberculosis5

intracanalicular

spread

to

Involve

the the may

ovaries

or

uterus.

Lesions

of

the

uveal

tract

and choroid of of the adrenals creatic tuberculosis and skin

eye may be noted produce Addisons may lead to signs

in some cases. disease, and of pancreatic

Involvement the rare paninsufficiency

pigmentation. Pat ho genesis of discussion occur in any by spreading must be kept focus that as Phthisiogenic and in In filtrates figure 6 it is seen that a

From wasting lesion Thus,

the

preceding

phthisis may may progress this possibility

organ in which any tuberculous through the contiguous tissue. in mind from the time of the until the the therapy present, or primary death of the and other of the patient not form be of patient. should limited tuber-

appearance This would depend by the culosis. upon

of the primary seem to Indicate the pathological of a lesion

process

designation

The The after have who It may secondary any

Secondary hematogenous

Hematogenous spread dissemination spread. lesion in

Spread is a term used in this that paper occurs who those lungs. postor

to indicate

hematogenous

of disease

the first hematogenous a progressive primary have lesions by one may the that in an first find a have area be Initiated

It may occur the lung as to other that mlllary parts has

in patients well as in of been the At tuberculosis

spread of infection hematogenous

previously

established mortem

hematogenous

dissemination.

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Vol.

xvii

THE

PATHOGENESIS

OF

TUBERCULOSIS

557 search find only a

tuberculous
small caseous

meningitis
process

and
in in any

after
bone,

thorough
kidney, prostate,

produced
Any unhealed

the stream.

overwhelming
lesion

infection
organ

by invading may progress

the

etc., that has blood stream. invade the

and

blood

Effect
In monia, children upper incidental respiratory

of

Non-Specific
disease infections, such

Diseases
as etc., non-tuberculous pneu-

may other

result hand, the

in

visible sputum or

progression may extension


is most The

of of
potent

disease. turn

In is less
activating

adults, likely spread.

on but to
tuberculous

the occur.

temporarily disease
in of

positive,

demonstrable Necrotizing
lesions.6

progression pneumonia
Satisfactory

collapse conclusion reading


tuberculous tion,

usually
presence

prevents
incidental

infections

may has
Loefflers

also of and

lead viral pleural

to

the

false

that chest
bacterial

tuberculous roentgenograms,
pneumonias,

disease the after

progressed.
eosinophilic

Certainly and noninfiltra-

in

possibility

lipiodal as mind. occur

reactions
in

bronchograms
lupus

effusions
be kept

such in

disseminated

erythematosis

must

The Failure has never incubation to react to

Negative

Tuberculin may
infection

tuberculin tuberculous percentage

signify or of patients

that is in

the the heal

individual preallergic their infec-

sustained period.

A small

Progressive Endo9enous bafion Exogenous

primary exacerreinfection

IInvolved
L Bronchial

regional

nodes

4
invasion

-i-Il

I1
Contiquous fhrough
Jr

spread +issue

Phthisis

Tube rcu lou s Pneumonia


FIGURE 6: Pathogenesis of Phthisis.

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558 tion may Infectious


miliary

CHARLES

M. NICE,

JR.

May,

1950

and

the

allergy negative such

subsequently temporarily as measles, meningitis, space following


or

disappears. as a result

The of

tuberculin an incidental

test

become
tuberculosis

disease the pleural technique never of

ing

of

in the late stages of generalized or after an overwhelming seedrupture of a subpleural focus. uncommon have without widely who factor. skin active for have Some allergy disease many controlled state to the years. a patients even protects This first in

Inadequate apparently the presence Whether the status infection, produce Individual may

Is not

an

or only intermittently active disease. to tuberculin been discussed in persons of has

sensitivity be attained

and the proponents the tuberculin reaction

BCG vaccination without harm

that they Individual.

FIGURE

7:

Composite

Pattern

of Possibilities.

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Vol.

XVII

THE

PATHOGENESIS of tuberculin and immunity co-exist to

OF TUBERCULOSIS sensitivity appear some degree. that more problem In a the than
has

559 been reported.7 to separate facsay that this allergy immunity danger.

Cellular Although tors2 they

transfer allergy usually

to

be

also due

Some

is dangerous, that co-exists Many studies controlled, but conclusions and proved discussion of

while with

others claim the allergy this that

protective offsets

discussing it is hoped

have been inadequately few years more scientific of the not be results, neglected. of this other paper. tried Further

may be methods this

drawn. Regardless of control must is beyond Discussion the

problem

scope

The nosis

study alone

of tuberculosis is often difficult

has

many to confusion poses an control

Interesting and in chest individual aspects find in the uniform of the in


its

facets. Garland8

The

diaglists manfor in the It the 89

establish,

conditions that have caused alone. Beyond this each case agement, endless controversial seems logical recognition culous to aid lesions one in of and discussion. public Many opinions that the a unified as the depicted study
SUMMARY

roentgenograms problem of form grounds lost However, and of of


aspects.

health expressed adoption

physicians of

themselves literature. terminology development form a basis


various

conception in of figure tuberculosis


AND

tuberthought

7 may

CONCLUSIONS infection has been discussed.

The Various omitted hoped

basic

pattern

of

tuberculous

theories of the mechanisms involved have been purposely in many instances, and indeed, many are unsolved. It is that further research and clinical observations will serve the evolution dogmatically or is the a in result of this disease. Although we may that a given lesion is a progressive of endogenous of the and exacerbation pathogenesis management or of of

to clarify further not be able to state primary exogenous tuberculosis each individual lesion

reinfection, will aid case.

unified concept the interpretation

RESUMEN Las Varias formas teorias b#{225}sicas de de los la

CONCLUSIONES infecciOn que se tuberculosa ponen en se juego discuten. se han no

mecanismos

omitido intenclonalmente est#{226}naclarados. Se

espera

y desde luego muchos que estudios ulteriores la evoluciOn para o es concepto de la asentar resultado patogenico

mecanismos y la observaclOn enfermedad. dogmaticamente de una de la infectuber-

cllnica servir#{225}n para aclarar Aunque estamos incapacitados si una lesiOn exOgena, es una primaria unificaciOn clOn

progresiva del

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560 culosis individual. The author wishes the National Jewish studying case material, Minnesota for helpful ayudara para

CHARLES

M.

NICE,

JR.

May,

1950

InterpretaciOn

y el tratamiento

de

cada

caso

to express gratitude to Dr. Allan Hurst and staff Hospital, Denver, Colorado, for the opportunity and to Dr. Jay Arthur Myers of the University guidance in the preparation of this paper. REFERENCES

of of of

J. A. and Waligren, A.: Pulmonary Tuberculosis in Adults and Children, Nelson Loose-Leaf Medicine, Thomas Nelson and Sons, New York. 2 Rich, A. R.: The Pathogenesis of Tuberculosis, Charles C. Thomas, Springfield, IllinoIs, 1944. 3 Caffey, J.: Pediatric X-ray Diagnosis, Year Book Publishers, 1945,
Chicago, Illinois.

1 Miller,

4 LevIne, M. I.: Sequence of Roentgen Evidence of Tuberculosis and Cutaneous Sensitivity to Tuberculin, Am. J. Dis. Child., 58:799, 1939. 5 Lincoln, D. M.: Hematogenous Tuberculosis in Children, Am. J. Dis. Child., 50:84, 1935. 6 Ornsteln, George G.: Hematogenous Dissemination of Tubercle Bacilli in Primary and Reinfection Forms of Tuberculosis, Sea View Hosp. Quart., 6:343, 1941. 7 Sweany, H. C.: Studies on the Nature of Primary Tuberculous Infection, Am. Rev. Tuberc., 27:559, 1933. 8 Auerbach, 0.: The Progressive Primary Complex, Am. Rev. Tuberc., 37:346, 1938. 9 Christlansen, N.: On the Different Forms of Phthisiogenous Infiltrates and the Development of Phthisis, Acta Rad., Vol. 30, Fasc. 1-2, 17-35, 1948. 10 Jullen-Marie, G. S. et Mathey, R.: LEmphyseme Bulleux Pseudocavitaire au cours de la Primo-Infection Tuberculeuse de LEnfant, Rev. de la Tub., Tome 12, No. 5-6, 331, 1948. 11 Jones, Edna M., Rafferty, T. N. and Willis, H. S.: Primary Tuberculosis, Complicated by Bronchial Tuberculosis with Atelectasis (Epituberculosis), Am. Rev. Tuberc., 46:392, 1942. 12 Gorgenyl-Gottche, 0. and Kasay, D.: Importance of Bronchial Rupture in Tuberculosis of Endothoracic Lymph Nodes, Am. J. Dis Child., 74:166, 1947. 13 Head, J. and Moen, C. W.: Late Non-Tuberculous Complications of Calcified Hilus Lymph Nodes, Am. Rev. Tuberc., 60:1, 1949. 14 Mann, K. J.: Lung Lesions in Skeletal Tuberculosis, Lancet, 2:744, 1946. 15 Ustvedt, H. J. and Wergeland, H.: Investigations on the Pathogenesis of Renal Tuberculosis, Acta Tbs., Vol. XXIII, Fasc. I, 36-62, 1949. 16 Baum, 0. S. and Baum, L. M.: The Effect of Non-Tuberculous Pulmonary Inflammation on Pulmonary Tuberculosis, Am. Rev. Tubere., 59:68, 1949. 17 Editorial: Cellular Transfer of Tuberculin Sensitivity, J.A.M.A., 141: 1301, 1949. 18 Garland, L. H.: Conditions to be Differentiated in the Roentgen Diagnosis of Pulmonary Tuberculosis, Ann. mt. Med., 29:878, 1948.

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