Acta Med Scand 206: 417-422, 1979
Miliary Tuberculosis Brita Stenius-Aarniala and Pentti Tukiainen From the Department of Pulmonary Diseases, University Central Hospitul, Helsinki, Finland
ABSTRACT. Twenty-six cases of miliary tuberculosis were studied in retrospect. The mean age of the Patients was 62 Years- Eighteen Patients suffered from another underlying chronic disease. Nine had been treated with corticosteroids or cytotoxic agents. A limited manifestation of tuberculosis had been previously verified or suspected in ten cases. Fever was present in 85 % of the patients, frequently combined with fatigue or abdominal pain. Serum alkaline phosphatase was elevated in 81 % of the cases. Minor haematological abnormalities (anaemia, etc.) were found in 16 cases and pancytopenia, stimulated lymphocytes or chronic myeloid leucaemia in six. Miliary mottling was found in the chest radiographs of 13 patients. Other findings were pleural effusion, mediastinal node enlargement, opacities suggesting pneumonia or old, possibly tuberculous lesions. Antituberculosis therapy was initiated in 12 patients, two of whom died within a few days. There was a high frequency of liver or system involvements. It is concluded that laparoscopy or liver needle biopsy are valuable diagnostic procedures in patients with fever and elevated alkaline phosphatases of unknown aetiology. A therapeutic test with antituberculous drugs should be undertaken in suspected cases.
and radiographic features were absent. It seemed that a “changing pattern” (7, 6) was becoming discernible in miliary tuberculosis, the disease often presenting as an obscure illness in the elderly. Having recently encountered diagnostically very difficult cases of disseminated tuberculosis, we decided to study the diagnostic aspect of all relevant cases seen at Helsinki University Central Hospital and Aw01-aHospital during the Past 7-Year period MATERIAL AND METHODS The material was collected with the help of the computer data on final diagnosis, coded according to international practice. In addition, 5000 final autopsy records were examined. The hospital records of all 25 cases traced in this way were available for retrospective study. The 26th patient, a man with miliary tuberculosis and respiratory distress syndrome, was referred for treatment and included in the material at a time when the present report was already under preparation. The material comprises 16 females and 10 males with a mean age of 62 years (range 41-80). The chest X-rays were re-analyzed by the authors.
Key words: miliary tuberculosis, respiratory distress syn-
drome. Acta Med Scand 206: 417, 1979.
During the last three decades several authors have drawn attention to miliary or disseminated tuberculosis as posing diagnostic problems ( 1 , 9, 11). MPkela et al. (8) described 129 fatal cases in which the principal cause of death was tuberculosis. In about 30% of the cases tuberculosis was not diagnosed until autopsy, and it appeared that miliary or disseminated tuberculosis constituted the majority of these undiagnosed cases. The concept of cryptic miliary tuberculosis was introduced by Proudfoot et al. ( 1 1) to designate cases of disseminated tuberculosis in which the typical clinical 27 -7929x5
RESULTS On admission the majority (85%) of the patients complained of fever (Table I). A body temperature of 39°C or higher was measured in 63% of the patients during the hospital stay. Fatigue, loss of weight and abdominal pain were each complaints of about one third of the patients. Eight patients complained of dyspnoea. One of these cases calls for more detailed comments. CASE REPORT A man aged 50, in whom cirrhosis of the liver had been diagnosed earlier, presented with fever and severe dyspnoea, rales being noted basally on both lung fields. His arterial PO, was 57 mmHg on inhalation of 35% oxygen Acto Mrd Scotid 206
418
B . Stenius-Aarniala and P. Tukioinen
Table I. Presenting symptoms in 26 c u e s of miliciry tuberculosis
Table 11. Haemutological findings in 26 miliary tuberculosis
No. of cases Fever (38°C) Loss of weight Abdominal pain Fatigue Dyspnoea Nausea and vomiting Cough Headache
23 10
9 9 8 6 4 3
through a Venti-mask. The chest radiograph showed enlarged upper mediastinum, faint hazy opacities basally on both sides, and a small parenchymal infiltration in the right lower lobe. The diaphragm was bilaterally elevated. Clinically, the patient suffered from the respiratory distress syndrome. Neither the dyspnoea nor the hypoxia responded to treatment with digitalis, diuretics, broadspectrum antibiotics or corticosteroids. After a few days of antituberculosis treatment the dyspnoea disappeared, and the auscultation finding was normal. Within 3 weeks the arterial 0, tension rose to 73 mmHg when the patient was breathing air. The diagnosis of tuberculosis was eventually confirmed when the patient’s condition allowed mediastinoscopy and a tuberculous glandular abscess was found.
ESR was elevated (mean 64.8 mmlh, range 14150) in 23 out of 26 cases, in 6 cases it was 100 mm/h
or higher. Alkaline phosphatase was elevated in 17 (81 %) out of the 21 patients who underwent the test (mean 919 U/l, range 318-2233). It should be pointed out that liver cirrhosis could account for the elevated value in 3 cases. Serum transaminase was normal in most cases. The tuberculin test was performed in only 10 cases, 1-2 TU being positive in 3 and 10 TU in another 3 cases. The frequency of haematological abnormalities (Table 11) in this series has to be evaluated in the light of the fact that, for various reasons, many patients were inadequately examined. The following haematological investigations had been performed: tests for Hb in 26 patients, total WBC in 23, differential count in 21, and thrombocyte count in 20. Bone marrow aspirate was examined in 1 1 patients and showed no specific abnormalities. An unspecific plasma cell reaction was found in 2 patients, one of whom also presented with pancytopenia. In the other case of pancytopenia in our material, the haematological diagnosis had been made and steroid treatment started 10 years prior to the
~ N S L J Sof
No. of cases No haematological changes Slight changes Anaemia “Shift to the left” Thromboc ytopenialthrombocytosis Leucocytosis Severe changes* Lymphoid cells in bone marrow Pancytopenia Chronic myeloid leucaemia
4“ 16
16 10
9 6 6
3 2 2
“ Only Hb was determined in two cases, Hb and total WBC in one case. Several of these findings were occasionally present in one and the same patient.
*
onset of miliary tuberculosis. In 2 cases, atypical lymphoid cells were found but no specific diagnosis was made. In both of these cases the autopsy diagnosis was CML in combination with disseminated tuberculosis. Miliary mottling was seen in the chest radiographs of 1 1 patients (37%) (Table 111). In 2 of these cases the chest radiograph was normal on admission, the mottling changes appearing at a later stage. In 2 cases the primary findings were pleural effusion and diffuse parenchymal infiltrates, respectively, miliary mottling appearing only after some time. In 2 cases an enlarged mediastinal shadow occurred in combination with miliary mottling.
Table 111. Chest radiographic findings in 26 coLses of miliary tuberculosis No. of cases Abnormal findings“ Miliary mottling or nodular shadowing Pleural effusion Enlarged mediastinal glands Parenchymal infiltrate interpreted as pneumonia “Inactive” pulmonary tuberculosis Fibrosis (scleroderma) Atelectasis (carcinoma of upper mediastinum) Normal
24 11 4 4
6 7 1 1
2
Several findings sometimes presented in one and the same radiograph.
(I
Milimy tuberculosis
419
Table IV. Source qf:finul diugnosis and ground f o r starting treutment in 26 cases of miliury tuberculosis No. of cases
Source of final diagnosis
Total
Bacteriological verification Pathologic-anatomical findings Both the above Clinical picture and/or X-ray finding alone Autopsy Total
2 4 3 1 16 26
Sixteen (58%) of the 26 cases were fatal (Table IV). In two cases, death was attributed to malignant disease and the miliary tuberculosis was taken to be a secondary finding. In 14 cases (54%) tuberculosis was diagnosed unexpectedly at the post mortem examination. In 7 cases treatment had been started ex juvantibus, and in 5 cases after the exact diagnosis had been made (Table V). The treatment was effective in almost all the treated cases. In two cases tuberculosis was not suspected until miliary
Treatment started ex juvantibus before specific diagnosis was established
Treatment started after specific Not diagnosis treated
1 2 1
1 2 2
1
2 7
5
14 14
mottling became apparent after several weeks of severe disease. Both these patients died shortly after antituberculosis treatment had been instituted. Three of 11 patients with symptoms for less than two months died against 7 of 15 with symptoms for a longer period. In the autopsied cases, tuberculosis was found in different organs in various combinations. Typical tuberculotic changes were found in the spleen, the liver or the peritoneal glands in all cases. In addi-
Table V. Source of diagnosis and course of diseuse in 12 treated cases of disseminated tuberculosis
(y.)
Miliary mottling on chest Sex X-ray
Diagnostic measures resulting in pathologicanatomical diagnosis
Results of tests for M. tuberculosis
68
0
Present
Cutting needle lung biopsy (TruCut)
40
6
Absent
Good, died 3 years later from perforation of the colon Good
65
P
Absent
63
0
Absent
Laparoscopy: spleen biopsy Laparoscopy : biopsy from peritoneum and lymph node Needle liver biopsy
Acid-fast smear from lung specimen positive, sputum culture positive Smear and culture from spleen specimen positive Culture from gastric lavage fluid positive
Good
68
6
Absent
Negative (sputum, urine, liver specimen) Negative (sputum, urine)
51
P
Present
50
d
Absent
12
0
Present
80 77 79
0 P P
Present Absent Present
-
73
0
Present
Autopsy
Age
Laparoscopy : spleen biopsy Cutting needle lung biopsy (TruCut) Mediastinoscopy : biopsy from hilar lymph node -
Autopsy
Response to treatment
Good
Negative (sputum)
Good, died of bleeding ventricular ulcer 3 months later Good
Negative (sputum)
Good
Culture positive from spinal fluid and gastric lavage Sputum culture negative Sputum culture positive Sputum culture positive, result not known until post rnortem -
Good Good Good Died within 4 days after initiation of treatment Died within 12 hours after initiation of treatment
420
B . Stc~t~iii.s-A~irniiilri rind P. TiiXicrinen
Table V1. Chronic discwses diugnosed prior to ($miliury tirberi~ulosi.~ in 26
onset o f the symptoms c'mses
NonSurvivors survivors (N) (N) Previously healthy Chronic disease Emphysema and TB pleurisy previously Diabetes and non-specific arthritis Rheumatoid arthritis Scleroderma and myeloid leucaemia Pancytopenia Hodgkin's disease Carcinoma Cirrhosis of the liver Chronic pyelonephritis and resection of the stomach earlier Chronic glomerulonephritis and uraemia Pemphigoid, erythema multiforme Diabetes and recurrent cerebrovascular thrombosis Schizophrenia Total
5"
3' 16
1 26
I* Id
1" Id
2
1d
Tuberculosis had been found or suspected in a total of 10 patients. The diagnosis of pleural, pulmonary or glandular tuberculosis was confirmed in 3 patients. A spontaneously healed tuberculosis was plausible in 7 patients, in whom either calcified lesions in the upper lobe were found, or a history of pleurisy, spondylitis, coxitis or fistulating lymphadenitis was present. One patient had a history of familial tuberculosis in 11 cases, many of them fatal. In several cases a pre-existing disease may have contributed to the diagnostic difficulties (Table VI). Three of the 16 patients who died of tuberculosis had previously been healthy, whereas this was the case in 6 out of 10 diagnosed, treated and surviving patients. Six patients had previously been treated with corticosteroids and three with cytostatics.
1
2 I0
1 1 10
16
Includes one patient lacking IgM and IgA and with low IgG values and one who possibly had previously suffered from tuberculous coxitis. 'I Treated with corticosteroids. ' Includes two patients with a possible history of tuberculosis disease (upper lobe calcification, fistulating lymphadenitis). Treated with antitumour chemotherapy. "
tion, involvement of the lung parenchyma, hilar glands or pleura was found in all cases except one. Other organs showing tuberculotic changes were the kidneys (4 cases), the suprarenal glands, the heart, the bone marrow ( 2 cases each), the brain, the meninges and the lumbar spine (spondylitis) (1 case each). I n the surviving patients the important diagnostic procedures were needle biopsy of the lung (TruCut), mediastinoscopy, laparoscopy, laparotomy or needle biopsy of the liver. In some of these cases therapy had been started before the diagnosis had been confirmed. Sputum specimens for bacteriologic examination had been taken from 17 cases. Three of these yielded positive cultures for TB bacilli, while all direct smears for acid-fast bacilli in sputum were negative.
DISCUSSION
All the patients included in this study were considered to be cases of miliary tuberculosis either by the clinician or, in the fatal instances, by the pathologist on the basis of the necropsy result. Sufficient evidence of disseminated spread of tuberculosis was, in our opinion, present in all survivors. Miliary tuberculosis is known to present frequently as pyrexia of unknown origin, though the fever is often only moderate (1, 10, 1 I). Contrary to patients described in other reports, most of those in our material ran a temperature of over 39°C at some stage of the disease. Loss of weight, fatigue, abdominal pain and dyspnoea are often reported in connection with miliary tuberculosis (10). This is supported by our findings. However, many of these symptoms and signs in our material could have been attributed to some other co-existing disease. Respiratory distress syndrome in connection with miliary tuberculosis has been described by several authors. Most of the cases have been fatal (4,5 ) , but de Silva et al. (15) described a patient who survived, the symptoms and signs of respiratory distress disappearing within 9 days of antituberculosis treatment. The patient with respiratory distress and miliary tuberculosis in our material is thus the second surviving case described in the literature. Elevation of alkaline phosphatase in serum in connection with miliary tuberculosis is thought to be a sign of infiltrative disease of the liver (13). It was found by Munt (9) in about 30% of the cases reported on. In our material elevated serum alkaline
Milimy t~berclr1osi.s
phosphatase was found in 81 c/o of the cases, confirming the results of Grieco and Chmel (3), who reported a percentage of 86. The tuberculin test was performed in less than half of our patients. All the tested cases belonged to age groups which were not covered by the BCG vaccination scheme instituted in Finland in 1941, and i t can be assumed that the positive tuberculin tests were not a result of vaccination. The results of possible previous tuberculin tests were not available for comparison. In the cases with negative tests, repeated testing at a later stage might have given positive results, as indicated by Glasser et al. ( 2 ) . Opinions differ concerning the interpretation of haematological abnormalities encountered in cases of disseminated tuberculosis. Anaemia, leucopenia, leucocytosis and monocytosis have been found to disappear as a result of antituberculosis treatment alone, and can thus be directly associated with tuberculosis ( 2 ) . Patients with leucaemic blood pictures or pancytopenia in the series of Glasser et al. ( 2 ) did not survive. In many cases it may be difficult to interpret whether the haematological abnormality is secondary to tuberculosis or whether it has constituted a predisposing factor. Anaemia and shift to the left were the commonest haematological features found in our material. The pancytopenia in one of our two patients had been diagnosed several years earlier. The other patient was treated with antituberculosis drugs which resulted in recovery and disappearance of the blood cell abnormalities. Miliary mottling is the classical finding in the chest X-ray in miliary tuberculosis. The absence of this sign is likely to add to the diagnostic difficulties. In 8 out of our 14 cases diagnosed at necropsy, the chest radiograph had not suggested miliary tuberculosis. However, when re-evaluated in retrospect, four of these 8 chest radiographs did reveal miliary mottling. Enlarged mediastinal glands have occasionally been associated with miliary tuberculosis and were present in 4 of our cases. This agrees with the results of Reed et al. (12) who found enlarged rnediastinal glands in three of 26 adult patients. Ophthalmoscopy as a means of detecting chorioidal tubercles was undertaken in only one case in our material, the result being negative. The bone marrow was frequently examined but the aspirated marrow was not fixed in paraffin, as suggested by
42 1
Schleicher (14) to facilitate the diagnosis of a possible tuberculosis from the marrow specimen. Most of our surviving patients were previously healthy or suffered from a chronic disease not giving symptoms indicative of disseminated tuberculosis. However, in many of the cases with a fatal course of miliary tuberculosis, the symptoms of fever, weight loss, haematological changes and abdominal pain were attributable to pre-existing disease. In one of our cases anaemia and, some months later, myeloid leucaemia were diagnosed during antituberculous treatment for lung tuberculosis. The antituberculosis drugs were at first thought to be the cause of the blood disorders and they were therefore withdrawn after 4 months of treatment. Attention was thereafter focused on the haematologic disease and after a few weeks of steroid therapy the patient died of miliary tuberculosis. This case resembles one presented by Munt (9) in which steroid treatment possibly enhanced the fatal miliary spread of tuberculosis from a previously diagnosed and treated lesion. The appearance of a new, severe disorder in a patient with tuberculosis may require transfer to another hospital, where several diagnostic and therapeutic problems have to be solved. It is understandable that the antituberculosis treatment may not be paid enough attention in such circumstances. In the fatal cases in our material the possibility of tuberculosis had-mostly because of other co-existing disease-not been taken under sufficient consideration. Many of the patients would eventually have succumbed to their severe chronic disease, but life might have been prolonged by some months or even some years, had the tuberculosis been treated. Our findings give reason to emphasize the importance of starting antituberculosis treatment in time; almost all the treated cases recovered. The results of the applied diagnostic tests and the autopsy findings indicate that laparoscopy may be a useful procedure in patients with fever and elevated alkaline phosphatase of unknown origin. In patients with diffuse pulmonary shadowing, needle biopsy of the lung may be valuable. If the patient’s condition does not allow these procedures, or if the results are negative, a therapeutic test with antituberculous drugs should always be undertaken. Miliary tuberculosis seems to be a condition which is chiefly found among elderly patients and which, in the presence of other severe chronic diseases, frequently escapes clinical detection.
422
B . Stenius-Aarniula and P. Titkininen
REFERENCES
8. Makela, V . , Ala-Kulju, K . , Holst, J. & Siljander, T.:
1. Bottiger, L. E., Nordenstam, H. H. &Wester, P. 0.:
2.
3.
4.
5.
6.
7.
Disseminated tuberculosis as a cause of fever of obscure origin. Lancet 1: 19, 1962. Glasser, R. M., Walker, R. I. & Herion, J. C.: The significance of haematological abnormalities in patients with tuberculosis. Arch Intern Med 125: 691, 1970. Grieco, M. H. & Chmel, H.: Acute disseminated tuberculosis as a diagnostic problem. A clinical study based on twenty-eight cases. Am Rev Respir Dis 109: 554, 1974. Homan, W., Harman, E., Braun, N. M., Felton, C. P., King, T. K. C. &Smith, J . P.: Miliary tuberculosis presenting as acute respiratory failure: Treatment by membrane oxygenator and ventricle pump. Chest 67: 366, 1975. Huseby, J . S. & Hudson, L. D.: Miliary tuberculosis and adult respiratory distress syndrome. Ann Intern Med 85: 609, 1976. Jacgues, J. & Sloan, J. M.: The changing pattern of miliary tuberculosis. Thorax 25: 237, 1970. Leading article: Miliary tuberculosis: a changing pattern. Lancet 1: 985, 1970.
Ac,frr Mrrl
Suitid
206
9.
10. 11.
12.
13. 14.
Tuberculosisaiagnosed and undiagnosed-as a cause of death. Autopsy observations. Scand J Respir Dis 52: 13, 1971. Munt, P. W.: Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American adults. Medicine 51: 139, 1971. Proudfoot, A. T.: Cryptic disseminated tuberculosis. Br J Hosp Med 5:773, 1971. Proudfoot, A . T., Akhtar, A. J., Douglas, A. C. I% Horne, N. W.: Miliary tuberculosis in adults. Br Med J 2: 279, 1969. Reed, M. H . , Pagtakham, R. D., Zylak, C. J. & Berg, T. J.: Radiologic features of miliary tuberculosis in children and adults. J Can Assoc Radio1 28: 175, 1977. Sahn, S. A. & Neff, T. A,: Miliary tuberculosis. Am J Med 56: 495, 1974. Schleicher, E. M.: Demonstration of tuberculosis in the human bone marrow. Improved technique. Minn Med 49: 221, 1966. de Silva, A., Gibson, J. & Gilbert, D. N.: Miliary tuberculosis and adult respiratory distress syndrome. Ann Intern Med 86: 659, 1977.
Miliary Tuberculosis Brita Stenius-Aarniala and Pentti Tukiainen From the Department of Pulmonary Diseases, University Central Hospitul, Helsinki, Finland
ABSTRACT. Twenty-six cases of miliary tuberculosis were studied in retrospect. The mean age of the Patients was 62 Years- Eighteen Patients suffered from another underlying chronic disease. Nine had been treated with corticosteroids or cytotoxic agents. A limited manifestation of tuberculosis had been previously verified or suspected in ten cases. Fever was present in 85 % of the patients, frequently combined with fatigue or abdominal pain. Serum alkaline phosphatase was elevated in 81 % of the cases. Minor haematological abnormalities (anaemia, etc.) were found in 16 cases and pancytopenia, stimulated lymphocytes or chronic myeloid leucaemia in six. Miliary mottling was found in the chest radiographs of 13 patients. Other findings were pleural effusion, mediastinal node enlargement, opacities suggesting pneumonia or old, possibly tuberculous lesions. Antituberculosis therapy was initiated in 12 patients, two of whom died within a few days. There was a high frequency of liver or system involvements. It is concluded that laparoscopy or liver needle biopsy are valuable diagnostic procedures in patients with fever and elevated alkaline phosphatases of unknown aetiology. A therapeutic test with antituberculous drugs should be undertaken in suspected cases.
and radiographic features were absent. It seemed that a “changing pattern” (7, 6) was becoming discernible in miliary tuberculosis, the disease often presenting as an obscure illness in the elderly. Having recently encountered diagnostically very difficult cases of disseminated tuberculosis, we decided to study the diagnostic aspect of all relevant cases seen at Helsinki University Central Hospital and Aw01-aHospital during the Past 7-Year period MATERIAL AND METHODS The material was collected with the help of the computer data on final diagnosis, coded according to international practice. In addition, 5000 final autopsy records were examined. The hospital records of all 25 cases traced in this way were available for retrospective study. The 26th patient, a man with miliary tuberculosis and respiratory distress syndrome, was referred for treatment and included in the material at a time when the present report was already under preparation. The material comprises 16 females and 10 males with a mean age of 62 years (range 41-80). The chest X-rays were re-analyzed by the authors.
Key words: miliary tuberculosis, respiratory distress syn-
drome. Acta Med Scand 206: 417, 1979.
During the last three decades several authors have drawn attention to miliary or disseminated tuberculosis as posing diagnostic problems ( 1 , 9, 11). MPkela et al. (8) described 129 fatal cases in which the principal cause of death was tuberculosis. In about 30% of the cases tuberculosis was not diagnosed until autopsy, and it appeared that miliary or disseminated tuberculosis constituted the majority of these undiagnosed cases. The concept of cryptic miliary tuberculosis was introduced by Proudfoot et al. ( 1 1) to designate cases of disseminated tuberculosis in which the typical clinical 27 -7929x5
RESULTS On admission the majority (85%) of the patients complained of fever (Table I). A body temperature of 39°C or higher was measured in 63% of the patients during the hospital stay. Fatigue, loss of weight and abdominal pain were each complaints of about one third of the patients. Eight patients complained of dyspnoea. One of these cases calls for more detailed comments. CASE REPORT A man aged 50, in whom cirrhosis of the liver had been diagnosed earlier, presented with fever and severe dyspnoea, rales being noted basally on both lung fields. His arterial PO, was 57 mmHg on inhalation of 35% oxygen Acto Mrd Scotid 206
418
B . Stenius-Aarniala and P. Tukioinen
Table I. Presenting symptoms in 26 c u e s of miliciry tuberculosis
Table 11. Haemutological findings in 26 miliary tuberculosis
No. of cases Fever (38°C) Loss of weight Abdominal pain Fatigue Dyspnoea Nausea and vomiting Cough Headache
23 10
9 9 8 6 4 3
through a Venti-mask. The chest radiograph showed enlarged upper mediastinum, faint hazy opacities basally on both sides, and a small parenchymal infiltration in the right lower lobe. The diaphragm was bilaterally elevated. Clinically, the patient suffered from the respiratory distress syndrome. Neither the dyspnoea nor the hypoxia responded to treatment with digitalis, diuretics, broadspectrum antibiotics or corticosteroids. After a few days of antituberculosis treatment the dyspnoea disappeared, and the auscultation finding was normal. Within 3 weeks the arterial 0, tension rose to 73 mmHg when the patient was breathing air. The diagnosis of tuberculosis was eventually confirmed when the patient’s condition allowed mediastinoscopy and a tuberculous glandular abscess was found.
ESR was elevated (mean 64.8 mmlh, range 14150) in 23 out of 26 cases, in 6 cases it was 100 mm/h
or higher. Alkaline phosphatase was elevated in 17 (81 %) out of the 21 patients who underwent the test (mean 919 U/l, range 318-2233). It should be pointed out that liver cirrhosis could account for the elevated value in 3 cases. Serum transaminase was normal in most cases. The tuberculin test was performed in only 10 cases, 1-2 TU being positive in 3 and 10 TU in another 3 cases. The frequency of haematological abnormalities (Table 11) in this series has to be evaluated in the light of the fact that, for various reasons, many patients were inadequately examined. The following haematological investigations had been performed: tests for Hb in 26 patients, total WBC in 23, differential count in 21, and thrombocyte count in 20. Bone marrow aspirate was examined in 1 1 patients and showed no specific abnormalities. An unspecific plasma cell reaction was found in 2 patients, one of whom also presented with pancytopenia. In the other case of pancytopenia in our material, the haematological diagnosis had been made and steroid treatment started 10 years prior to the
~ N S L J Sof
No. of cases No haematological changes Slight changes Anaemia “Shift to the left” Thromboc ytopenialthrombocytosis Leucocytosis Severe changes* Lymphoid cells in bone marrow Pancytopenia Chronic myeloid leucaemia
4“ 16
16 10
9 6 6
3 2 2
“ Only Hb was determined in two cases, Hb and total WBC in one case. Several of these findings were occasionally present in one and the same patient.
*
onset of miliary tuberculosis. In 2 cases, atypical lymphoid cells were found but no specific diagnosis was made. In both of these cases the autopsy diagnosis was CML in combination with disseminated tuberculosis. Miliary mottling was seen in the chest radiographs of 1 1 patients (37%) (Table 111). In 2 of these cases the chest radiograph was normal on admission, the mottling changes appearing at a later stage. In 2 cases the primary findings were pleural effusion and diffuse parenchymal infiltrates, respectively, miliary mottling appearing only after some time. In 2 cases an enlarged mediastinal shadow occurred in combination with miliary mottling.
Table 111. Chest radiographic findings in 26 coLses of miliary tuberculosis No. of cases Abnormal findings“ Miliary mottling or nodular shadowing Pleural effusion Enlarged mediastinal glands Parenchymal infiltrate interpreted as pneumonia “Inactive” pulmonary tuberculosis Fibrosis (scleroderma) Atelectasis (carcinoma of upper mediastinum) Normal
24 11 4 4
6 7 1 1
2
Several findings sometimes presented in one and the same radiograph.
(I
Milimy tuberculosis
419
Table IV. Source qf:finul diugnosis and ground f o r starting treutment in 26 cases of miliury tuberculosis No. of cases
Source of final diagnosis
Total
Bacteriological verification Pathologic-anatomical findings Both the above Clinical picture and/or X-ray finding alone Autopsy Total
2 4 3 1 16 26
Sixteen (58%) of the 26 cases were fatal (Table IV). In two cases, death was attributed to malignant disease and the miliary tuberculosis was taken to be a secondary finding. In 14 cases (54%) tuberculosis was diagnosed unexpectedly at the post mortem examination. In 7 cases treatment had been started ex juvantibus, and in 5 cases after the exact diagnosis had been made (Table V). The treatment was effective in almost all the treated cases. In two cases tuberculosis was not suspected until miliary
Treatment started ex juvantibus before specific diagnosis was established
Treatment started after specific Not diagnosis treated
1 2 1
1 2 2
1
2 7
5
14 14
mottling became apparent after several weeks of severe disease. Both these patients died shortly after antituberculosis treatment had been instituted. Three of 11 patients with symptoms for less than two months died against 7 of 15 with symptoms for a longer period. In the autopsied cases, tuberculosis was found in different organs in various combinations. Typical tuberculotic changes were found in the spleen, the liver or the peritoneal glands in all cases. In addi-
Table V. Source of diagnosis and course of diseuse in 12 treated cases of disseminated tuberculosis
(y.)
Miliary mottling on chest Sex X-ray
Diagnostic measures resulting in pathologicanatomical diagnosis
Results of tests for M. tuberculosis
68
0
Present
Cutting needle lung biopsy (TruCut)
40
6
Absent
Good, died 3 years later from perforation of the colon Good
65
P
Absent
63
0
Absent
Laparoscopy: spleen biopsy Laparoscopy : biopsy from peritoneum and lymph node Needle liver biopsy
Acid-fast smear from lung specimen positive, sputum culture positive Smear and culture from spleen specimen positive Culture from gastric lavage fluid positive
Good
68
6
Absent
Negative (sputum, urine, liver specimen) Negative (sputum, urine)
51
P
Present
50
d
Absent
12
0
Present
80 77 79
0 P P
Present Absent Present
-
73
0
Present
Autopsy
Age
Laparoscopy : spleen biopsy Cutting needle lung biopsy (TruCut) Mediastinoscopy : biopsy from hilar lymph node -
Autopsy
Response to treatment
Good
Negative (sputum)
Good, died of bleeding ventricular ulcer 3 months later Good
Negative (sputum)
Good
Culture positive from spinal fluid and gastric lavage Sputum culture negative Sputum culture positive Sputum culture positive, result not known until post rnortem -
Good Good Good Died within 4 days after initiation of treatment Died within 12 hours after initiation of treatment
420
B . Stc~t~iii.s-A~irniiilri rind P. TiiXicrinen
Table V1. Chronic discwses diugnosed prior to ($miliury tirberi~ulosi.~ in 26
onset o f the symptoms c'mses
NonSurvivors survivors (N) (N) Previously healthy Chronic disease Emphysema and TB pleurisy previously Diabetes and non-specific arthritis Rheumatoid arthritis Scleroderma and myeloid leucaemia Pancytopenia Hodgkin's disease Carcinoma Cirrhosis of the liver Chronic pyelonephritis and resection of the stomach earlier Chronic glomerulonephritis and uraemia Pemphigoid, erythema multiforme Diabetes and recurrent cerebrovascular thrombosis Schizophrenia Total
5"
3' 16
1 26
I* Id
1" Id
2
1d
Tuberculosis had been found or suspected in a total of 10 patients. The diagnosis of pleural, pulmonary or glandular tuberculosis was confirmed in 3 patients. A spontaneously healed tuberculosis was plausible in 7 patients, in whom either calcified lesions in the upper lobe were found, or a history of pleurisy, spondylitis, coxitis or fistulating lymphadenitis was present. One patient had a history of familial tuberculosis in 11 cases, many of them fatal. In several cases a pre-existing disease may have contributed to the diagnostic difficulties (Table VI). Three of the 16 patients who died of tuberculosis had previously been healthy, whereas this was the case in 6 out of 10 diagnosed, treated and surviving patients. Six patients had previously been treated with corticosteroids and three with cytostatics.
1
2 I0
1 1 10
16
Includes one patient lacking IgM and IgA and with low IgG values and one who possibly had previously suffered from tuberculous coxitis. 'I Treated with corticosteroids. ' Includes two patients with a possible history of tuberculosis disease (upper lobe calcification, fistulating lymphadenitis). Treated with antitumour chemotherapy. "
tion, involvement of the lung parenchyma, hilar glands or pleura was found in all cases except one. Other organs showing tuberculotic changes were the kidneys (4 cases), the suprarenal glands, the heart, the bone marrow ( 2 cases each), the brain, the meninges and the lumbar spine (spondylitis) (1 case each). I n the surviving patients the important diagnostic procedures were needle biopsy of the lung (TruCut), mediastinoscopy, laparoscopy, laparotomy or needle biopsy of the liver. In some of these cases therapy had been started before the diagnosis had been confirmed. Sputum specimens for bacteriologic examination had been taken from 17 cases. Three of these yielded positive cultures for TB bacilli, while all direct smears for acid-fast bacilli in sputum were negative.
DISCUSSION
All the patients included in this study were considered to be cases of miliary tuberculosis either by the clinician or, in the fatal instances, by the pathologist on the basis of the necropsy result. Sufficient evidence of disseminated spread of tuberculosis was, in our opinion, present in all survivors. Miliary tuberculosis is known to present frequently as pyrexia of unknown origin, though the fever is often only moderate (1, 10, 1 I). Contrary to patients described in other reports, most of those in our material ran a temperature of over 39°C at some stage of the disease. Loss of weight, fatigue, abdominal pain and dyspnoea are often reported in connection with miliary tuberculosis (10). This is supported by our findings. However, many of these symptoms and signs in our material could have been attributed to some other co-existing disease. Respiratory distress syndrome in connection with miliary tuberculosis has been described by several authors. Most of the cases have been fatal (4,5 ) , but de Silva et al. (15) described a patient who survived, the symptoms and signs of respiratory distress disappearing within 9 days of antituberculosis treatment. The patient with respiratory distress and miliary tuberculosis in our material is thus the second surviving case described in the literature. Elevation of alkaline phosphatase in serum in connection with miliary tuberculosis is thought to be a sign of infiltrative disease of the liver (13). It was found by Munt (9) in about 30% of the cases reported on. In our material elevated serum alkaline
Milimy t~berclr1osi.s
phosphatase was found in 81 c/o of the cases, confirming the results of Grieco and Chmel (3), who reported a percentage of 86. The tuberculin test was performed in less than half of our patients. All the tested cases belonged to age groups which were not covered by the BCG vaccination scheme instituted in Finland in 1941, and i t can be assumed that the positive tuberculin tests were not a result of vaccination. The results of possible previous tuberculin tests were not available for comparison. In the cases with negative tests, repeated testing at a later stage might have given positive results, as indicated by Glasser et al. ( 2 ) . Opinions differ concerning the interpretation of haematological abnormalities encountered in cases of disseminated tuberculosis. Anaemia, leucopenia, leucocytosis and monocytosis have been found to disappear as a result of antituberculosis treatment alone, and can thus be directly associated with tuberculosis ( 2 ) . Patients with leucaemic blood pictures or pancytopenia in the series of Glasser et al. ( 2 ) did not survive. In many cases it may be difficult to interpret whether the haematological abnormality is secondary to tuberculosis or whether it has constituted a predisposing factor. Anaemia and shift to the left were the commonest haematological features found in our material. The pancytopenia in one of our two patients had been diagnosed several years earlier. The other patient was treated with antituberculosis drugs which resulted in recovery and disappearance of the blood cell abnormalities. Miliary mottling is the classical finding in the chest X-ray in miliary tuberculosis. The absence of this sign is likely to add to the diagnostic difficulties. In 8 out of our 14 cases diagnosed at necropsy, the chest radiograph had not suggested miliary tuberculosis. However, when re-evaluated in retrospect, four of these 8 chest radiographs did reveal miliary mottling. Enlarged mediastinal glands have occasionally been associated with miliary tuberculosis and were present in 4 of our cases. This agrees with the results of Reed et al. (12) who found enlarged rnediastinal glands in three of 26 adult patients. Ophthalmoscopy as a means of detecting chorioidal tubercles was undertaken in only one case in our material, the result being negative. The bone marrow was frequently examined but the aspirated marrow was not fixed in paraffin, as suggested by
42 1
Schleicher (14) to facilitate the diagnosis of a possible tuberculosis from the marrow specimen. Most of our surviving patients were previously healthy or suffered from a chronic disease not giving symptoms indicative of disseminated tuberculosis. However, in many of the cases with a fatal course of miliary tuberculosis, the symptoms of fever, weight loss, haematological changes and abdominal pain were attributable to pre-existing disease. In one of our cases anaemia and, some months later, myeloid leucaemia were diagnosed during antituberculous treatment for lung tuberculosis. The antituberculosis drugs were at first thought to be the cause of the blood disorders and they were therefore withdrawn after 4 months of treatment. Attention was thereafter focused on the haematologic disease and after a few weeks of steroid therapy the patient died of miliary tuberculosis. This case resembles one presented by Munt (9) in which steroid treatment possibly enhanced the fatal miliary spread of tuberculosis from a previously diagnosed and treated lesion. The appearance of a new, severe disorder in a patient with tuberculosis may require transfer to another hospital, where several diagnostic and therapeutic problems have to be solved. It is understandable that the antituberculosis treatment may not be paid enough attention in such circumstances. In the fatal cases in our material the possibility of tuberculosis had-mostly because of other co-existing disease-not been taken under sufficient consideration. Many of the patients would eventually have succumbed to their severe chronic disease, but life might have been prolonged by some months or even some years, had the tuberculosis been treated. Our findings give reason to emphasize the importance of starting antituberculosis treatment in time; almost all the treated cases recovered. The results of the applied diagnostic tests and the autopsy findings indicate that laparoscopy may be a useful procedure in patients with fever and elevated alkaline phosphatase of unknown origin. In patients with diffuse pulmonary shadowing, needle biopsy of the lung may be valuable. If the patient’s condition does not allow these procedures, or if the results are negative, a therapeutic test with antituberculous drugs should always be undertaken. Miliary tuberculosis seems to be a condition which is chiefly found among elderly patients and which, in the presence of other severe chronic diseases, frequently escapes clinical detection.
422
B . Stenius-Aarniula and P. Titkininen
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