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Dahlmans, R.P.M.

Frantzen, P.J.

Koopman, R.J.J.

Meer, J.W.M. van der

Rietbroek, R.C.

Smedts, F.

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Tuberculosis cutis miliaris disseminata as a manifestation of miliary tuberculosis : literature review and report of a case of recurrent skin lesions

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265
REVIEW  ARTICLES
Tuberculosis Cutis Miliaris Disseminata as a Manifestation of Miliary 
Tuberculosis: Literature Review and Report of a Case of Recurrent 
Skin Lesions
R. C. Rietbroek, R. R M. Dahlmans, F. Smedts, 
R J. Frantzen, R. J. J. Koopman, 
and J. W. M. van der Meer
From the Departments o f Medicine, Pathology, and Dermatology, 
Division o f General Internal Medicine, University Hospital Nijmegen, 
Nijmegen; and the Asthma Centre and Clinic for Chronic Respiratory
Diseases, Hornerheide, Horn, The Netherlands
The development of severe adverse reactions to antituberculous drugs in a patient with miliary 
tuberculosis led to unorthodox, suboptimal antituberculous therapy. The patient’s failure to re­
spond to therapy was discovered when acid-fast bacilli were detected in new skin lesions. Such 
lesions have been described in the literature as tuberculosis cutis miliaris disseminata; 24 cases 
(in addition to that described herein) have been reported thus far. The patient eventually recov­
ered completely after detection and drainage of a large retrofascial tuberculous abscess. This 
case illustrates the importance of careful examination of the skin in clinical medicine, as tubercu­
losis cutis miliaris disseminata is an easily overlooked sign of miliary tuberculosis.
We recently treated a patient in whom severe adverse reac­
tions to antituberculous drugs led to unorthodox, suboptimal 
antituberculous therapy. The failure of therapy was discov­
ered when acid-fast bacilli were detected in new skin lesions. 
Such lesions, which are a rare manifestation of miliary tuber­
culosis [1], have been described in the literature as tuberculo­
sis cutis miliaris disseminata. This form of disease is usually 
associated with a poor prognosis and was seen more often 
before antituberculous drugs became available [1].
Case Report
A 64-year-old woman had had systemic sclerosis and poly­
myositis since 1985, for which she received prednisone (25 
mg/d) and azathioprine (150 mg/d). In July 1988 she had been 
admitted to another hospital with high fever, rigors, and fa­
tigue. She had no history of dyspnea or tuberculosis. On phys­
ical examination she was found to be ill, with no abnormalities 
except acrosclerosis.
Laboratory investigation revealed an erythrocyte sedimen­
tation rate of 46 mm (Westergren; normal rate, <12 mm after
1 hour) and normal hepatic and renal function. Radiography 
of the chest showed diffuse reticulonodular infiltrates in both 
lungs. The reaction to purified protein derivative (PPD, 10 U
Received 8 February 1990; revised 21 May 1990.
Reprints and correspondence: Dr. R. C. Rietbroek, Department of Medi­
cine, Division of General Internal Medicine, University Hospital Nijme­
gen, Postbox 9101, 6500 HB Nijmegen, The Netherlands.
Reviews of  Infectious Diseases 1991;13:265-9 
©  1991 by The University of Chicago. All rights reserved.
0162-0886/91/1302-0011502.00
given intracutaneously) was negative. Bronchoalveolar lavage 
yielded acid-fast bacilli.
The diagnosis of miliary tuberculosis was made. Therapy 
was started with rifampin, pyrazinamide, isoniazid, and 
pyridoxine. On day 10 the administration of these drugs was 
stopped because of disturbances of hepatic function. The level 
of serum aminotransferases was more than four times the nor­
mal value. Treatment with ethambutol and streptomycin was 
started. On day 15 flucloxacillin and gentamicin were ad­
ministered because of blood cultures positive for Staphylo­
coccus aureus; these findings were related to the presence 
of an intravenous catheter. Three days later gentamicin treat­
ment was stopped, and, because of persistent fever, ceftazi­
dime and amikacin were added to the regimen. In retrospect, 
it is clear that the attending physician paid too little attention 
to the cumulative toxicity of the aminoglycosides used dur­
ing this period.
On day 17 the patient developed disseminated erythema­
tous macules and papules (diameter, 5-10 mm) on her legs, 
arms, and trunk. There were more lesions on the lower half 
of the body. A skin biopsy showed a deep dermal infiltrate 
composed of granulocytes and lymphocytes intermingled with 
histiocytes and a protein-rich exudate. Ziehl-Neelsen stain­
ing revealed dispersed acid-fast bacilli. No caseation necro­
sis or vasculitis was present, and there were no tuberculous 
granulomas. Biopsied skin tissue was not cultured.
A subsequent bone marrow biopsy showed a granuloma­
tous inflammation. However, no caseation necrosis or vascu­
litis was evident, and Ziehl-Neelsen staining gave negative 
results. Cultures of urine and feces were negative. Because 
of the skin lesions, therapy with isoniazid was restarted at 
a dose of 300 mg/d.
Three days later the patient’s level of consciousness declined
266 Rietbroek eî al. R1D 1991;13 (M arch-April)
progressively. Results of cerebral computed tomography and 
lumbar puncture were within normal ranges, and electroen­
cephalography yielded findings consistent with a metabolic 
encephalopathy. Renal insufficiency was diagnosed (estimated 
creatinine clearance rate, 6 mL/min), and amikacin treatment 
was stopped.
On day 28 the still-comatose patient was admitted to our 
ward. Because isoniazid was considered to be the most likely 
cause of the coma, all medication except prednisone (25 mg/d) 
was stopped. Pyridoxine (125 mg) was given intravenously. 
Over the course of several days, the patient regained conscious­
ness; on day 33 therapy with rifampin, ethambutol, and strep­
tomycin was recommenced, with doses adjusted to renal 
function. When it became apparent that there was a hearing 
loss consistent with aminoglycoside toxicity, streptomycin 
treatment was stopped.
Culture of bronchoalveolar lavage fluid yielded a strain of 
Mycobacterium tuberculosis sensitive to all antituberculous 
drugs.
Although the chest radiograph clearly improved and the skin 
lesions gradually disappeared, the patient remained febrile. 
For this reason a third antituberculous drug was thought to 
be necessary, and ciprofloxacin was given in a dose of 500 
mg/d.
On day 70 a small group of erythematous and purpuric pap­
ules (5-10 mm in diameter) appeared on the upper part of 
both thighs (figure 1). A careful examination of the skin re­
vealed no other lesions. Biopsies yielded results the same as 
those obtained initially; panniculitis without granulomas and 
with many tubercle bacilli was noted (figure 2). The culture 
of the biopsy specimen remained negative. Because of these 
findings, isoniazid (300 mg every 48 hours) was restarted; 
3 weeks later, when renal function had improved, the drug 
was given once a day. Ethambutol administration was stopped.
On day 124 the patient was transferred to a clinic for chronic 
respiratory diseases. Her medication at this point consisted 
of prednisone, isoniazid, rifampin, and ciprofloxacin. The 
chest radiograph was almost normal, and the skin lesions were 
regressing. The remaining problem was fever (maximum, 
39.7°C) that occurred at irregular intervals (approximately 
two or three times a week).
Because of the possibility of drug fever, the use of isonia­
zid and rifampin was stopped for several days, but this change 
had no apparent effect. The only new sign during this period 
was a nonhealing ulcer—thought to be decubital — on the left 
buttock. Nevertheless, skin obtained at biopsy of this lesion 
on day 132 showed a dermal granulomatous inflammation with 
acid-fast bacilli. A culture was negative. Therapy remained 
unchanged; on day 157, after 3 months, ciprofloxacin treat­
ment was stopped.
Beginning on day 163, the patient complained of pain in 
the left popliteal fossa. She gradually developed a swelling 
there, which expanded when she was standing and disappeared 
when she was lying down. The swelling was not warm or red.
Figure 1. Top: Erythematous and purpuric papules on right up­
per thigh, a manifestation of tuberculosis cutis miliaris disseminata. 
Bottom: Detail of papule, with size in centimeters.
Radiography of the legs and pelvis showed no signs of os­
teomyelitis. Computed tomography on day 197 showed a large 
retrofascial abscess originating in the gluteal muscles and 
descending along the musculus biceps femoris to the left 
popliteal fossa (figure 3). There were no abscesses in the ab­
domen or retroperitoneum. No osseous destruction was seen. 
It could not be ascertained whether previous intramuscular 
injections of streptomycin had contributed to the formation 
of this cold abscess.
On day 202 the abscess was incised, yielding 1,400 mL of 
debris with acid-fast bacilli. Cultures remained negative, in­
cluding those for aerobic and anaerobic bacilli. Ethambutol 
(800 mg/d) was added to the regimen on day 204. After inci­
sion of the abscess, the fever disappeared.
On day 246 the patient was discharged in good condition 
without skin lesions. Her medication at discharge consisted 
of rifampin, isoniazid, ethambutol, pyridoxine, and pred­
nisone.
RID 1991;13 (M arch-Apri l) Skin Lesions in Miliary Tuberculosis 267
Figure 2. Punch biopsy specimen 
from a skin lesion. The epidermis 
is intact. In the deeper dermis, 
there is an infiltrate of granulocytes 
and lymphocytes intermingled 
with histiocytes and protein-rich 
exudate (hematoxylin and eosin; 
magnification, x25). Inset: Many 
fluorescent tubercle bacilli can be 
seen (auramine stain, fluorescent 
technique; magnification, xlOO).
Discussion
In the case of miliary tuberculosis reported herein, skin 
manifestations typical of tuberculosis cutis miliaris dissemi­
nata were seen. As described in the literature and observed 
in this case, these lesions are discrete, dull, erythematous mac­
ules and papules that are initially the size of a pinhead. They 
may become capped by tiny vesicles that, after rupturing, leave 
papules with a central crust. Removal of this crust reveals 
a minute but sharply defined umbilication or dell. In this case 
no vesicles were observed. The lesions are most frequently 
localized on thighs, buttocks, genitalia, and extremities. Their 
number is usually no more than 20-30. Pustules and nodules 
have also been described in some instances [1-3].
These lesions are caused by the hematogenous dissemination 
of tubercle bacilli as a cutaneous manifestation of general­
ized miliary visceral tuberculosis [1-3]. Histologic examina­
tion shows a nonspecific dermal infiltrate of lymphocytes and
plasma cells, with focal areas of necrosis and abscess (usu­
ally without granuloma formation) in which acid-fast bacilli 
are found [1-14]. Granuloma formation seems to be depen­
dent on the presence of vascular thrombi with acid-fast bacilli, 
which interrupt the local blood supply. Blockage of the cir­
culation seems to cause necrosis, thereby rendering a specific 
tuberculoid reaction impossible [1].
A negative PPD reaction is a typical finding in tuberculosis 
cutis miliaris disseminata, in contrast to other forms of cuta­
neous tuberculosis and tuberculids, which are associated with 
a positive skin reaction [1-3].
Through a computer search of the literature (Medlars), we 
found reports on 24 cases of tuberculosis cutis miliaris dis­
seminata [1, 2, 4-14]. The characteristics of these cases are 
given in table 1. In two cases (10 and 21) no biopsies were 
performed, and in five cases (7, 11, 12, 23, and 24) no acid- 
fast bacilli were demonstrated; thus a meaningful evaluation 
of these seven cases is impossible.
Figure 3. Computed tomography of the upper legs. 
In the left upper leg (seen on the right here) is an ab­
scess (*) extending along the musculus biceps femoris. 
This is an extension from a large retrofascial abscess 
in the gluteal muscles on the left side.
268 Rietbroek et al. RID 1991;13 (March-April)
Table 1. Reported cases of tuberculosis cutis miliaris disseminata 
in patients >15 years old.
Patient Age/sex AFB
PPD
reaction
Anti­
tuberculous
drugs
Healing
skin
Fatal
outcome
Refer­
ence
1 22/M + NS No No Yes 1
2 29/M + NS No No Yes 4
3 35/F + NS No No Yes 4
4 2 9 /M + NS No No Yes 1
5 36/M + NS No No Yes 1
6 63/F + NS No No Yes 5
7 46/F — NS No No Yes 6
8 37/M + — No No Yes 7
9 29/F + NS No No Yes 8
10 50/M NS NS S No Yes 9
11 20/M — NS P/S/I Yes No 9
12 6 9 /M — NS S/P No Yes 9
13 71/F + NS No No Yes 9
14 21/M + NS P / S - I * Yes No 9
15 57/M + ----- No No Yes 9
16 16/M + ----- S/P Yes No 9
17 18/M + ----- S/P Yes No 9
18 30 /M + ----- P/S/I Yes Yes 1
19 31/F + / - NS R/E/I Yes No 2
20 20 / F + + R/S/I Yes No 10
21 36/F NS ----- E/S/I Yes No 1 1
22 67/M -1- ----- R/E/I Yes No 12
23 58/M ----- + R/E/I/PY Yes No 13
24 32/M ----- ----- R/E/I No Yes 14
NOTE. Abbreviations: AFB = acid-fast bacilli; + =  positive; -  = negative; 
+ / -  =  indeterminate; NS = not stated: S =  streptomycin; P -  /¿-aminosalicylic 
acid: I =  isoniazid; R =  rifampin; E =  eihambutol; PY =  pyrazinamide.
* The therapeutic agent was changed from P/S to I.
A positive PPD reaction was reported in two cases (20 and 
23) and a negative PPD reaction in eight cases; no PPD data 
were given for the remaining 14 cases. Healing of the cutane­
ous lesions usually occurred at 4 -6  weeks (range, 2 weeks 
to 10 months).
Recurrences were not described, with the possible excep­
tions of cases 14 and 17 [1, 2, 9-13]. In case 14 new lesions 
appeared every few weeks despite repeated courses of strep­
tomycin and /^-aminosalicylic acid; after 2 years, isoniazid 
was given, and no additional lesions developed subsequently. 
In case 17 new lesions appeared in the first month after initia­
tion of antituberculous therapy.
Therefore, the recurrence of skin lesions in this form of 
tuberculosis is unusual. It is interesting that the reappearance 
of skin lesions was initially the only sign of insufficient ther­
apy in the case we have described herein.
In the reported cases, major underlying illnesses were vir­
tually absent. In case 21 there was a history of alcohol abuse, 
and in cases 9 and 23 there was a history of previous tuber­
culous infection [8, 11, 13]. No other reports of tuberculosis 
cutis miliaris disseminata in immunocompromised patients 
were found in the literature, although dissemination of tuber­
culous infection to the skin would theoretically be expected 
to occur more frequently in such patients. In our patient the 
use of glucocorticosteroids and azathioprine seems to have 
been a major factor in the failure to control mycobacterial 
infection.
The tuberculous ulcer on the left buttock of our patient can 
be interpreted as a manifestation of tuberculosis cutis miliaris 
disseminata. It can also be accounted for, however, by local 
spread of bacilli from the underlying abscess, a scenario de­
scribed elsewhere as tuberculosis cutis colliquativa [1-3].
The cold tuberculous abscess in our patient was unusual 
in two respects. First, it was located behind the fascia in the 
gluteal folds, with extension downward to the popliteal fossa. 
Usually, spontaneous drainage occurs more proximally, to­
ward the insertion of the glutei on the greater trochanter or 
at the posterior aspect of the proximal part of the femoral shaft 
[15]. Second, there was no infection of the sacrum, the ilium, 
or the sacroiliac joint, which are the most common sources 
of retrofascial abscess [15, 16]. A retroperitoneal source was 
also excluded. Hematogenous dissemination of acid-fost bacilli 
to the gluteal region is probably the best explanation.
The most likely reason for the failure of therapy in this pa­
tient with recurrent skin lesions is a combination of subop­
timal regimens [17, 18] and the presence of a tuberculous 
abscess —a source of recurrent bacteremia. We were greatly 
limited in our choice of drugs by hepatotoxicity, nephrotox­
icity, ototoxicity, and CNS toxicity in this patient. After the 
partial restoration of renal function, we were able to use isonia­
zid, rifompin, and ciprofloxacin, and skin lesions subsequently 
improved. Only after the detection of the large abscess and 
surgical therapy was complete recovery possible. This case 
illustrates the risk of ototoxicity and nephrotoxicity when 
different aminoglycosides are given simultaneously.
The cause of coma in this case remains speculative. Isonia­
zid metabolites, which accumulated during the period of re­
nal insufficiency [18], were probably responsible.
This case illustrates the importance of careful examination 
of the skin in clinical medicine, since tuberculosis cutis miliaris 
disseminata is an easily overlooked sign of miliary tubercu­
losis.
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Tuberculosis cutis miliaris disseminata as a manifestation of miliary tuberculosis : literature review and report of a case of recurrent skin lesions

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