TUBERCLE THE J O U R N A L OF
THE BRITISH TUBERCULOSIS A S S O C I A T I O N
A STAPLES
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The Time-Table of Tuberculosis
By ARVID WALLGREN
Professor of Pediatrics, Royal Caroline Medical Institute, Stockholm, Sweden
Infection by the tubercle bacillus leads, in
the majority of cases, to a reaction that is
innocuous for the infected person. The
resultant primary tuberculous disease soon
heals, and the infection has then run its
course for that particular irldividual. In
such cases the tuberculous infection is
m e r e l y an episode without significance and
its pathological manifestations are sub-
clinical or are not observed. The majority
o f tuberculin-positive cases have no idea of
w h e n and under what circumstances they
were infected. This is the benign extreme
of the general picture of tubercukms infec-
tion.
The other grave extreme occurs when the
infection leads to various clinical morbid
conditions at its first manifestatior~ and
subsequently the infected person may pass
tkrough a series of primary, early and late
post-primary tuberculous diseases, and may
ultimately succumb to phthisis.
Between these two extremes we find the
majority of clinically manifest tuberculous
infections. The infection gives rise to a
t e m p o r a r y illness of longer or shorter dura-
tion and, if the disease heals completely, it
is then latent or subclinical, as in the first
type o f extreme benign infection.
Age Difference
T h e resistance of the infected person
determines the course of the tuberculous
infection, i.e. whether it is to remain sub-
clinical or whether a morbid condition will
ensue. The nature of the disease that
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develops in those with the least resistance is
influenced to a large degree by the age of
the infected person. Meningitis is rare in
adults but rather common in irtfants mid
small children with tuberculous infection.
Pleurisy never occurs during the firsu year
of life and is uncommon during tlxe secbnd,
but it occurs frequently before azld durivag
school-age, at least in certain countries such
as the Scandinavian. Platllisis scarcely ever
occurs during the first ten years of life, but
is common during puberty, adolescence,
early adulthood, &c. The organism reacts
to tuberculous infection in distinctly different
ways at different ages and different stages of
development of the infected. Hence it is
possible in some degree to determine before-
hand the manifestations of a tuberculous
disease.
Manifestly, however, it is not solely the
infected person's age and resistance that
determine whether a certain disease will
develop. Various forms of the disease m a y
occur too in different individuals belonging
to the same age-group, seemingly without
conforming to any law. It is evident that
other factors also play a part in the occur-
rence of certain types of disease. I propose
mainly to deal with one of those factors
today, namely the significance of the age of
the tuberculous infection. The beginning of
a tuberculous infection, i.e. the exact time
at which the infection occurs, is known
accurately only in a small minority of cases.
It is possible, however, to draw certain con-
clusions from tlle time at which the infection
246 TUBERCLE
reaches a certain stage, and thus to deter-
mine its starting-point. T h e first stage is the
manifestation of tuberculin sensitivity; it is
a fixed point which very frequently can be
determined exactly by various means. In
those cases in which it is possible during the
period of incubation to follow an infection
by serial tuberculin tests, the m o m e n t when
the reaction changes from negative to posi-
tive is directly observable and the end of the
incubation period can be determined to
within a few days. But the opportunity to
keep check on an infected person in this
way before tuberculin sensitivity is mani-
fested occurs only in exceptional cases, and
most commonly in children.
Fixing of Infection Date
However, in a very large number of cases
other means exist of determining the point
of time in question. When the infection, in
the course o f its development, reaches the
end of the incubation period, certain signs
are usually present, and for one who knows
how to interpret these signs it is possible to
obtain from them a basis on which to judge
when that period will end. These signs,
however, are not of such a nature that tlley
can readily be identified as tuberculous
phenomena; they are non-specific. But when
properly correlated they are so pronounced
that they should not pass unobserved. If the
significance of these signs is properly under-
stood, they might provide diagnostic guid-
ance and lead to further examinations
demonstrating that they have been in-
terpreted correctly. The signs in question
are e r y t h e m a nodosum and initial fever.
Erythema Nodosum
A good deal has been written on the
subject of e r y t h e m a nodosum in Britain,
and, as far as I have been able to ascertain,
the Swedish conception of this phenomenon
is now more or less consistent with that of the
entire medical world; wherefore I need only
briefly refer to the subject here. Erythema
nodosum is to be regarded as a non-specific
allergic p h e n o m e n o n which, with relativeIy
November 1948
few exceptions, appears as a manifestation
of tuberculous allergy. In Sweden, sensitivity
to tuberculin is absent only in roughly 5 per
cent of the erythema nodosum cases. In
these exceptional cases the erythema conse-
quently must be of another origin than
tuberculosis. By comparing the onset of
erythema after infection, one finds that it
coincides with the first manifestation of
sensitivity to tuberculin at the end of the
incubation period.
Initial Fever
Erythema nodosum, when occurring as
a sign at the end of the incubation period,
is a relatively unusual phenomenon by
comparison with the large number of
primary infections. When erythema nodosum
occurs, it is almost invariably accompanied
by fever. Initial fever without erythema
nodosum is a far more common phenomenon,
particularly in children. According to a
statistical analysis made at my clinic several
years ago, only one of" 25 cases of primary
infection showed a positive tuberculin test
without passing through a febrile period.
Primary infections in cases past childhood
assuredly run their course more often
without fever. The fever which constitutes
the most usual clinical sign that a tuberculous
infection has just passed the incubation
period is, as is probably well known, not in
any way characteristic. It might be of very
short d u r a t i o n - o n l y a few d a y s - o r it
might last for several weeks; it might be
slight, only a few decimal points above
normal temperature, or it might be very
high; it might be continual or it might be
remittant. There is no possibility of recog-
nizing it as an initial fever unless one is able
to demonstrate that the tuberculin reaction
had previously been negative but had
changed to positive concurrently with the
fever period, or unless one is at the same
time able to observe the manila,station of
primary tuberculosis.
The physician who realizes how common
initial fever is, and who has often seen very
early primary tuberculosis overlooked simply
November 1948 TUBERCLE
because of the neglect to make tuberculin
tests, himself makes those tests and recom-
mends others to dr) so on all formerly
tuberculin negative or non-tested claildren
who fall ill with fever. In such cases the
suspicion of initial fever very of'ten proves to
have been warranted, and the investigator
is rewarded with a positive tuberculin re-
action. It may seem inconvenient and un-
necessary to perform tuberculin tests in all
such cases of fever. Fortunately, however,
the investigation is considerably facilitated
by the fact that tuberculin sensitivity, on
the manifestation of the primary infection,
is usually so marked that the convenient
percutaneous or cutaneous tests are suffi-
ciently sensitive to reveal the presence of
tuberculous allergy. In a series of early
primary tuberculosis cases in children, there
were only two of one hundred who failed to
show positive reaction m the simple tuber-
culin-ointment test. Hence, if such. tests are
carried out in cases with. acute lizver, there
will be better prospects of recognizing the
cause of' the fever as tuberculous.
Sedimentation Rate
Still another non-specific phenomenon
accompanies the manifestation of the primary
infection and is to be regarded as a sign,
namely a rise in the sedimentation rate.
This occurs even in cases in which a careful
check on temperature at the end of the
incubation period has disclosed no fever. I
have seen cases of illness in children in
which the routine sedimentatiort test on an
apparently fully healthy child has formed
the basis for a more thorough examination
with special consideration to tuberculosis,
and in which it has been possible to establish
primary tuberculosis. If the aforementioned
signs- erythema nodosum, initial fever and
an initial rise in sedimentation r a t e - a r e
correctly interprete, d and automatically
lead to tuberculin tests in cases previously
tuberculin negative or not tested, then the
point at which the incubation period is due
to end will be revealed. Th, e first stage in
the coursc of a tuberculous infectio~l has
247
then been passed. It enables us, moreover,
to determine t h e starting-point, i.e. when
15:'
I0-
13
La
...0
2 5-
2 3 4 5 6 7 s 9 wee~
Manifestation-time of Primary Tuberculosis
after infection.
tb.e infection occurred. This took place
between three and eight weeks earlier. A
lengthy series of observations, evaluated
carefully and critically, have shown that
the incubation period in most cases lasts
between five and six wceks, though in
exceptional cases it may be as short as thrce
weeks or as long as eight weeks.
Streptomycin treatment during the in-
cubation period makes it possible to prolong
that period and perhaps to extittguish the
infection before it manifests itself in tuber-
eulin sensitivity. In one of our cases treated
M t h streptomycin during the incubation
period, it was possible to demonstrate a
prolongation of that period up to four
months. This is probably the ideal juncture
at which to start streptomycin treatment,
but intervention at such an early stage
unfortunately is possible only in exceptional
cases.
Dissemination
Wlxen the primary infection manifests
itself, it is attended by a hematogenous
generalization of tb.e tubercle bacilli from
the primary complex; indeed, this process
assuredly continues for a short time there-
after, and possibly takes place somewhat
earlier too. It is seldom possible to demon-
strate tkis directly by means of blood cultures
248 TUBERCLE November 1948

but rather by clinical observation and by
certain tests for the presence of bacilli in
organs remote from the p r i m a r y complex.
Titus Rudbgck, working at my hospital with
a special technique described b y Silverstolpe,
25
20-
5.
culous meningitis in which the time of infec-
tion or of the change in tuberculin reaction
is known, they are found to be manifested
within three months of the last-named
juncture. During these months the course
of the tuberculosis evidently goes through a
pathologic process, which is manifested in
tuberculosis developing haematogenously.
When an infected person has survived this
period successfully, he is not likely to
contract tuberculous meningitis or miliary
tuberculosis. A very dangerous stage l~as
been passed; the infection has entered a
quieter and less risky period.

, 2 a 4 5 6
Manifestatlon-time o f Tuberculous l~IenJngi~is
a f t e r p r i m a r y tuberculosis.
was able to demonstrate, in several cases of
early p r i m a r y tuberculosis, a transient
excretion of virulent tubercle bacilli in the
otherwise fully normal urine and without
subsequent clinical signs of tuberculous
lesions in the kidneys. T h e tubercle bacilli
must have reached the kidneys via the blood
stream, and their excretion in the urine
therefore points to haematogenous dis-
sernination. Since these cases otherwise have
in no way differed fi'om other primary
tuberculosis cases, it seems probable that
subclinical haematogenous generalization
also occurs in the latter, even
though no excretion of bacilli in 201
the urine has been demonstrable.
What leads added weight to ~ ,5
the theory of the haematogenous
dissemination of tubercle bacilli 2 L0
7 e months Pleurisy
For the great majority of infected persons
this brings, concurrently with decreasing
activity, the gradual clinical healing of the
infection, which has thereby reached the end
of its course for that particular individual.
However, the passing of the haematogenous
danger zone constitutes, for the infected
person, merely a direct transition to another
period of clinical manifestations, namely
the pleurisy period. Just as miliary tuber-
culosis and meningitis may develop at any
time in an infected person, so may acute
tubercular serofibrinous pleurisy be mani-
fested at different times during the course
of tuberculosis. It has, however, a certain
41

concurrently with the manifest- "~

ation of primary tuberculosis is Z 5:
the number of acute haemato- " ,,, I

genous tubercular diseases that II

occur at this .juncture. Predi- J 2 3 4 5 6 7 a 9 Io ii 12 >t2 m o n t h s
lection to acute miliary tubercu- M a n i f e s t a t i o n - t i m e o f Pleurisy after p r i m a r y tuberculosis.
losis and tuberculous meningitis
seems to occur at this time. Each of typical time of appearance in most cases. In
these diseases m a y develop, it is true, at the vast majority of cases, the onset of
arty time after the manifestation of the pleurisy occurs three months after the
p r i m a r y infection; but in the great majority manifestation of the primary infection, and
o f cases of miliary tuberculosis and tuber- numerous cases develop during the ensuing
November 1948 TUBERCLE
three to four months. Thus the pleurisy
period follows immediately upon the menin-
gitis period, and in point of fact it is only in
extremely rare instances that art infected
person who has had pleurisy later falls ilI
with meningitis.
It is not known why the predilection
period of pleurisy occurs three to seven
months after the manifestation of the
primary infection. The development of
pleurisy presupposes a specific infection of
the pleura. Jacobaeus and Carstensen, by
thoracoscopy of the pleural cavity in cases of
acute pleuritis, have directly demonstrated
the presence of tubercular nodules in the
pleura. The onset of tuberculous peritonitis
and the conditions under which it develops
do not differ fi'om pleurisy; similarly, the
dissemination of tubercles has been observed
in the peritoneum during the therapeutic
laparotomies which in the past were often
performed in cases of peritonitis. The
demonstration of tubercle bacilli in the
pleural and peritoneal fluids, which has been
possible in roughly one-third of all cases
merely by performing routine tests, shows
that it is a question of a specific infection of
the serous membranes. Pleurisy usually
develops on the same side as that to whicl~
the primary pulmonary tuberculosis was
localized. Hence it seems probable that the
pleura of that side only was infected in the
aforementioned way. This presupposes a
more local association between primary
complex and pleural infection on the same
side, which can scarcely be explained ottler
than by assuming that the tubercle bacilli
have been disseminated lymphogenously,
or by direct local infection fi'om the primary
complex.
A specific infection of the pleura, however,
cannot adequately explain the development
of pleurisy. Pleurisy, both clinically and
anatomically, is a specific tuberculous pro-
cess. The clinical course of the disease, with
its acute febrile onset reminiscent of croupous
pneumonia, does not, however, resemble the
picture of plem'al tuberculosis. In animals,
infection of the pleura by tubercle bacilli
249
induces pleural tuberculosis and not tuber-
culous pleurisy. Evidently something more
than infection of the pleura is needed. In
pleurisy as in croupous pneumonia the
impression of hypersensitivity reaction is
conveyed. Moreover, pleurisy nowadays is
widely regarded as an allergic manifestation
with a specific tuberculous basis. T h e
occurrence of acute tuberculous pleurisy
evidently presupposes two factors, namely a
specific tuberculous infection of the pleura,
and a specific hypersensitivity of the pleura.
T h e question may arise as to why pleurisy
usually develops three to seven months after
the manifestation of the primary infection.
Is it because the plem'a has not been infected
earlier, or because hypersensitivity has not
developed i11 the pleurae until then, several
months later than the hypersensitivity in the
lungs and skin? If it is due to infection of the
pleura, we must assume that for some reason
it is attended by increased activity in the
course of the infection, facilitating the
infection of the pleura. There are certain
clinical observations which suggest such a
process. At the same juncture one observes
with increasing frequency that the primary
tuberculous lesions give rise to atelectasis,
assuredly signifying an increased enlarge-
ment of the hilus or bronchial glands
through heightened activity in the tubercu-
lous glandular process. This in turn may
indicate that the tuberculous infection has
entered a new phase, with greater intensity
of reaction in the organism, perhaps con-
stituting a sign that the haematogenous
disseminatior~ has been overcome.
It seems scarcely probable that the
allergic hypersensitivity in the pleura, only
would develop several months later than
the hypersensitivity in skin and lungs. In
serum sickness the symptoms may manifest
themselves in attacks at more or less free
intervals, which possibly indicates that the
hypersensitivity or those factors which it
involves show undulating intensity, some-
times giving rise to pronounced hyper-
sensitivity and sometimes to little or none.
Some phenomenon of a similar kind may
250 TUBERCLE November 1948

possibly cxplailt why the pleura is more a large number r skeletal tuberculosis cases,
markedIy ltypersensitive just at the m:tset of in width tim time of inIhctiott or of the
pleurisy. change in tuberculin reaction is known, we
The course of tuberculosis is characteristic find that this seemingly irregular course
ila other respects too, dm"illg the pleurisy nevertheless cotffonrts to certain laws,
stage. The duration os the fever as a rule is Tuberculosis in tb,e bones and jtJints is very
remarkably uniform in mlcomplicated cases. prone to develop during a certain period of
Generally it lasts roughly three weeks and is the course of tuberculosis, and when. this
followed on the whole by normal tempera- period has been passed the risk of this fi)rm
ture. The pleurisy itself is, of cmwse, ~['much of tuberculosis is no longer great. In the
longer duration. This fairly unilbrm period vast majority of caves, tuberculosis irt the
of fever indicates in turn that, in pleurisy it bones mid ,ioitlts develops during the first
is a case of some other morbid process thtm year after tim man.ifestatiort of the primary
tlle usual tuberculosis pleurae, an.d bespeaks ilffection; in a very larg'e numtmr of cases
the signifiemme of hypersensitivity in the during the secmtd year, and iu the remai~lder
pleura for the development of plem'isy, during the third year,
Primary tuberculosis as a rule is 1tot
Non-Pulmonary Disease active lbr more ttmt~ ~)lu: year at most.
Whetl the pleurisy has healed in dtese Tubercle bacilli are seld()m dem(mstraMe
individuals, and Mmn the same period has after that juncture, ht um:oml)licated cases
elapsed for those not sutlhring with pleurisy, both sedimentation, rate and temperature
tire tl,ornaal, What is unquestiojmbly the
7,0~ most active stage of primary tuberculosis
6fl
has been passed, In tylfical cases distilmt
signs of regressiott of the tuberculous lesimls,
with sclerosin.g of' neerotk' parts, appear
,,~ 48
during the second year. Only on. rare
occasions is the tuberculous ill[~:t't[otl then
active. In such cases the primaw tubercutosis
heals completely cluring the third yem',
leavittg calcifications in its trail. During this
year, of course, active tuberculosis is even
more rare in uncomplicated cases. It would
2 3 4 6 LJeo,r S
5
tlms seem that skeletal tuberculosis closely
Manifestation.time os Bone and Joint Tuberculosis follows the course of primary tuberculosis.
after primary tuberculosis.
It is most common when primary tuber-
culosis is most active; the further tlle
the tuberculous infection enters a latetlt healing process of the primary tuberculous
stage which as a rule leads to complete lesions has advanced, the less frequently it
clinical healing of that infection. In excep- appears; and it scarcely ever develops after
tional cases this latent phase is interrupted the complete healing of those lesions. When
b y new morbid processes of various ki,lds. tlle tuberculous infection has passed tlle
One such phenomenon, wlfich seems m~t to three-year mark there is no longer any
be limited in any major degree to individuals appreciable risk ol' skeletal tuberculosis.
of certain ages, is tuberculosis in the bones Other tuberculous conditions either occur
and joints. This develops ill inI'ants and may so rarely dtat only in very lhw cases are data
develop in aged persons. It appears to occur available ott which to fix the date of their
with seemingly complete irregularity during appearance in relatkm to the manifestation
the course of tubert:ulosis. But it" we examirm ot' the infection, for example urogenital
I~lovember 1948 TUBERCLE 251

tuberculosis and lupus; or are more passes througk a certain number of

d e p e n d e n t or[ the patient's age than the characteristic periods, in the course of wkich
a g e of the infection, for example tertiary specific tuberculous conditions appear con-
p u l m o n a r y tuberculosis, so that it is scarcely secutively with increasing frequency, whereas
~0
the risk of falling ill after the period that is
so characteristic of the disease in question
5O rapidly diminishes. The first stage is reached
~o five to six weeks after the infection and is
indicated by symptoms typical of the mani-
30 festation of primary tuberculosis: tuberculin
~g
E sensitivity, initial fever, erythema nodosum
, ~ 20"

II 2 3
|
4
II
5 6 ~et3r&
and primary complex. The second stage,
which follows immediately upon the first
and lasts roughly tkree months, coincides
with malignant generalized forms of tuber-
Manifestatlon-time of Pulmonary Tuberculosis culosis: miliary tuberculosis and meningitis.
after primary tuberculosis. The third stage, namely the pleurisy period,
follows immediately upon the second, com-
possible to classify such conditions in mencing about three months after the mani-
relation to the course of the disease. festation of the primary infection and lasting
approximately four months. The fourth
Phthisis stage lasts undl the primary complex has
I f we eliminate the age factor by selecting healed, i.e. roughly three years after infection
a group of newly infected cases and restrict- and commences concurrently with the first
ing it to certain a g e s - for instance between stage; this is the period of skeletal tuberculosis.
In persons with primary infection i~ their
t h e ages of 15 and 2 o - w e are in a better
adolescence, the fourth stage also corres-
position to ascertain whether there is any
regularity in the time for the onset of ponds to the period of post-primary pul-
phthisis. By making such a comparison it monary tuberculosis.
Knowledge of this chronological sequence
will be found that most cases occur during
the first three years after the manifestation of different tuberculous diseases is not only
of theoretical but also of practical interest,
o f the primary infection, but that cases also
develop later with rapidly decreasing fre- since it may serve as one of the guiding
quency. The conditions are thus reminiscent principles in making the prognosis. An
of those of skeletal tuberculosis. But in a infected person who is just passing the pre-
mixed case material, i.e. one in which the dilection period of a certain type of tuber-
time of infection varies in all the different culous disease runs a far greater risk of
age-groups, the time of onset will be so contracting that disease than he does after
camouflaged by the immensely significant having passed the period in question. In
age factor that it will not emerge so dis- several diseases, however, as for instance
tinctly. However, the smaller the difference meningitis, miliary tuberculosis and phthisis,
in time between primary infection and onset another chronological factor-the age of
of pulmonary tuberculosis, the more dis- the infected person-plays a dominating
tinctly will the characteristic interval between part. The correlation of these two factors
them emerge. lends further stability and certainty to the
Summary prognosis, which of course is also influenced
To sum up, it may be said that the by a number of other circumstances not
tuberculous infection ir~ an infected person treated here.