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Atypical mycobacteria as a probable cause of chronic bone disease
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September 1964
T h e J o u r n a l of P E D I A T R I C S
A typical myco bacteria as a probable cause of chronic bone disease A report oJ two cases
Two cases o[ chronic and apparently inflammatory bone and lung disease are presented in which the offending organisms are thought to be atypical mycobacteria. Scotochromogens were found in smears and cultures of material obtained from the bone lesions and gastric washings. The patients had features which appear to be characteristic of infections due to atypical mycobacteria, i.e., paucity of symptoms, poor response to antituberculosis therapy, and chronicity. The two cases strongly suggest that these organisms have the ability to cause bone disease. It is felt that awareness of this possibility will probalby uncover other cases in which the demonstration of "yellow" acid-fast bacilli would otherwise be attributed to accidental contamination.
Ingeborg Krieger, M.D.,* Otto H. Hahne, M.D., and Charles F. Whitten, M.D. DETROIT~ M I C H .
I N R E C E N T years m u c h attention has been focused on a group of atypical acid-fast bacilli (AFB), the photochromogenic, scotochromogenic, nonphotochromogenic mycobacteria, and rapid growers? These acid-fast organisms were formerly considered to be nonpathogenic. Evidence from cases of chronic pulmonary disease strongly suggests that atypical AFB are potentially pathogenic, for they have been present consistently in sputum or else have been the sole microor-
From the Pediatric Department of Detroit Receiving Hospital and the Herman Kie[er Hospital, Tuberculosis Division. "~Address, Wayne State Unlversity School of Medicine, c/o Children's Hospital of Michigan, 5224 St. Antoine St., Detroit 2, Mich.
ganism in resected lung specimens. 1-12 Furthermore, the occurrence of cervical adenitis due to these organisms is now well documented. 12-17 Apparently, only 5 cases have been reported in which atypical AFB were found in specimens obtained from bone lesions? s-22 Three patients h a d fatal systemic disease associated with disseminated osteomyelitis due to a nonchromogenic AFB 21, 22 or an organism possibly belonging to the Nocardia groupY ~ Since so few observations have been made relative to the possibility of an association between bone disease and atypical mycobacteria, the following two cases are reported. T h e features c o m m o n to these cases are: chronic osteomyelitis, chronic lung
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disease, a n d the presence of a scotochromogen in gastric washings a n d in smears a n d cultures of m a t e r i a l o b t a i n e d from the bone lesions. CASE 1 N. B. was a 5-year-old Negro boy who presented with swelling of the dorsum of the right hand for 2 months and of the left foot for 3 weeks. Physical findings. The physical examination revealed a well-developed, well-nourished boy in apparent good health. Temperature, pulse, and respiration were normal. A firm, indurated, nontender swelling was felt over the ulnar aspect of the dorsum of the right hand. A similar swelling was present dorsolaterally over the left metatarsal area. There was mild generalized lymphadenopathy with marked enlargement of the left inguinal and right epitrochlear nodes. The remainder of the physical examination, ineluding a complete ophthalmologic examination, was negative. Laboratory findings. On admission, the hemoglobin was 11.6 Gm. per cent. The red blood cell count was 4.26 million per cubic millimeter; reticulocyte count, 1.4 per cent; leukocyte count, 4,900 per cubic millimeter with 58 per cent polymorphonuclear neutrophils, 29 per cent lymphocytes, and 13 per cent eosinophils. The bone marrow showed an acceleration of myeloid leukogenesis which was not diagnostic. The urinalysis was negative. The serum glucose, urea nitrogen, total protein, albumin/globulin ratio, caIcium, phosphorus, and alkaline phosphatase Were normal. Tests for heterophil and febrile agglutinins and the Kline test were negative, as were skin tests for blastomycosis, histoplasmosis, and coccidioidomycosis. Skin tests with old tuberculin (1 : 1,000 and 1: 100) were negative. Radlologic examinations. Roentgenograms of the chest taken on admission and one week later showed diffuse perihilar densities (Fig. 1) and an area of increased density in the left lower lobe. A bone survey, taken on admission, showed a large medullary defect in the fourth right metacarpal diaphysis with expansion of this portion of bone, but absence of periosteal reaction. The proximal diaphysis was affected to a lesser degree. The radial diaphysis showed an illdefined lucent area occupying the posterior and medial portion of the medullary canal next to the cortex. There was expansion of bone at this
34 1
point, but no cortical destruction or periosteal reaction (Fig. 2). X-rays of the left foot showed cortical destruction and expansion of the fifth metatarsal bone without periosteal reaction (Figs. 3 and 4). The remainder of the bone survey was negative. Further studies. On the fifth hospital day a right axillary lymph node was removed for biopsy and showed noncaseating granulomatous tissue, with epithelioid ceils and a few giant cells. On the tenth hospital day biopsies of the metacarpal and metatarsal lesions were performed. These revealed numerous noncaseating granulomas with replacement of bone in some areas (Fig. 5). The histopathologic appearance of the lymph node, metacarpal and metatarsal lesions was compatible with the diagnosis of sarcoidosis. Although no acid-fast bacteria were detected in the sectioned material, a smear of the biopsy materiaI obtained from the metacarpal lesion did reveal acid-fast organisms. (The smear from the metatarsal lesion was negative.) Unfortunately, this report did not come immediately to the attention of the medical staff. The anaerobic culture grew out micrococci and the aerobic culture coagulase-negative Staphylococcus albus and a-streptococci. Hospital course. A presumptive diagnosis of sarcoidosis was made and the child was treated with steroids for 2 months. In addition erythromycin was given for a short time postoperatively. His hospital course was uncomplicated except for development of moon facies and occasional temperature spikes to 101 ~ F. The operative wounds healed well but the metacarpal and metatarsal swellings persisted, Two and one-hail months after admission the culture of material from the metacarpal lesion
Fig. 1. Case 1. Chest x-ray, taken on admission, showing densities in the perihilar region and left lower lobe.
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Fig. 2. Case 1. X-ray of the right hand showing medullary defects and expansion of bone, most prominent in the distal portion of the fourth metacarpal diaphysis. Ill-defined lucent area in the posterior and medial portion of the radial diaphysis, adjacent to the cortex, which is intact. Minimal expansion of bone at this point. No periosteal reaction present at either site.
Figs. 3 and 4. Case 1. X-rays of the left foot, taken on admission, showing cortical destruction and expansion of the fifth metatarsal bone without periosteal reaction. showed a "TB-like organism growing in smooth, wet appearing colonies." In the inoculated guinea pig it produced localized le~ions around the injection site, but no progressive disease. The organism was classified as a nonvirulent chromogen (niacin negative, catalase actively positive).* The cultures obtained from the metatarsal lesion and *Identification through the Bacteriology Laboratories, Department of Health, Herman-Kiefer Hospital, Detroit, Mieh.
September 1964
the initial gastric washing did not grow out organisms. X-rays taken at this time showed a small patch of density remaining in the left lower lobe adjacent to the diaphragm. Roentgenograms of the involved bones showed a slight decrease in the size of the previously described radiolucencies. Sclerosis, evidenced by increasing densities in areas surrounding the lytic defect, was present in both the metacarpal and metatarsal lesion. In view of the culture report, which suggested an etiologic relationship with an acid-fast organism, two and one-half months after admission the patient was transferred to a tuberculosis sanatorium and given isoniazid ( I N H ) , 350 mg., and para-amino salicylic acid (PAS), 3.5 Gm. per day. Laboratory tests remained essentially normal, except for mild, persistent eosinophilia of 3 to 6 per cent. Skin tests with old tuberculin (1:1,000 and 1:100) and with the purified protein derivate (0.0001) were repeated on several occasions and were consistently negative. Ten months after the original admission, signs of an acute inflammation of the left foot developed. Pus draining from the left foot was cultured and produced a hemolytic Micrococcus pyogenes var. aureus and Gaffkya tetragena. Only one culture for acid-fast organisms was performed on the drainage material and it was negative. Cultures of one of the two gastric washings performed at this time revealed atypical, niacinnegative AFB. The patient was treated with bed rest and wet compresses. Antituberculosis therapy was continued and no antibiotics were given. The sinus closed within 3 weeks but subsequently reopened and drained intermittently. Exactly one year after the original admission, x-rays of the chest revealed a persistent parenchymal infiltrate in the basilar region on the left (Fig. 6). The right radius showed a persistent, though less pronounced, radiolucent defect. The fourth right metacarpal and fifth left metatarsal bones revealed sclerotic lesions with spotty radiolucencies, prominent trabecular pattern, and intact cortical margins. The one gastric washing performed at this time was negative for AFB. The patient was discharged and one month later all therapy was discontinued. Seven months after discharge a swelling was first noted over the lateral aspect of the dorsmn of the right hand. The patient's general condition was good, and there was no local tenderness. An x-ray of the hand showed no change in the appearance of the bone lesion. Antituberculosis therapy ( I N H and PAS) was reinstituted
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Fig. 5. Case 1. Representative section of granulomatous tissue (metacarpal lesion). Poorly defined granuloma, fairly well vascularized, composed almost exclusively of epithelioid cells and inflammatory ceils. Absence of caseation necrosis. Mutinucleated giant cells were sparse, poorly formed, with rarely more than three nuclei present in one plane.
on an ambulatory basis. A few months later, i.e., approximately 2 years from the onset of the original illness, the mother noted an indolent swelling to the right of the bridge of the nose, which increased in size, while the patient was apparently still under antituberculosis therapy. Subsequently the foot started draining again, a draining sinus formed over the original lesion in the right hand, and the facial lesion broke through the hard palate. The patient, who had temporarily been lost to follow-up care, was finally readmitted to the sanatorium. The physical examination showed persistent, generalized lymphadenopathy. The epitrochlear nodes were palpable on both sides. Physical findings were otherwise limited to the three areas of osseous involvement in the hand, foot, and face. Inflammatory signs were mild; the swellings of the hand and foot were plum size, hard, and nontender. There was a hard, almond-size protuberance medial and inferior to the inferior orbital ridge. The hard palate was ulcerated, showing a midline oval sinus opening with granulated edges. Drainage from the three sites was intermittent and minimal. Material from these three draining lesions was examined for AFB on smear and culture four times each within the ensuing six months. Scotochromogens *
were cultured from the hand, foot, and palate each in one of these four specimens. Acid-fast bacilli were also demonstrated on a smear of drainage material from the foot. The scotochromogens were resistant to I N H , PAS, streptomycin,
~Identification through the Bacteriology Laboratories, Department of Health, Herman-Kiefer Hospital, Detroit, Mich.
Fig. 6. Case 1. Lateral chest x-ray, taken one year after admission, showing persistent parenchymal infiltrate in the basilar region on the left.
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Fig. 7. Case 1. Photograph of the right hand showing the ulcerative lesion with chronic draining sinus and surrounding skin nodules. viomycin, ethionamide, cycloserine, kanamycin, and pyrazinamide. Cultures for fungi were negative. A Staphylococcus aureus (phage type 5280) was cultured twice from the draining lesion of the hand. The material from the lesion of the hand was negative on dark-field examination for spirochetes. Eight gastric washings were performed. Scotochromogens were cultured in 2 of the washings at a time when the draining sinus in the hard palate showed the same organism. Radiologic examination of the fourth right metacarpal and fifth left metatarsal bones showed no significant change. There was expansion of bone with numerous spotty radiolucencies. A latteral view of the skull showed a foamy-appearing bone lesion with a thin outer shell protruding from the anterior wall of the maxillary antrum, which was itself thickened and contained minute radiolucencies. A new area of radiolucency was discovered in the distal portion of the left humerus, which was similar to that seen originally in the right radial diaphysis in that the cortex was intact. The previously lucent area in the right radius showed sclerosis and some cortical thickening. Skin tests for Group I - I I I atypical mycobacteria "x were negative. Skin tests for the following diseases were repeated a n d again negative: histoplasmosis, coccidioidomycosis, blastomycosis, and brucellosis. Serum concentrations of immune globulins were normal. Antituberculosis therapy was continued as before. Streptomycin was added, but discontinued after a period of 3 months. The patient subsequently developed eight small subcutaneous nodules, four in the area of the draining hand *Supplied by Lydia Edwards, Department of Health, Education, and Welfare, Tuberculosis Program, Washington, D.C.
September 1964
lesion (Fig. 7) and four in the region of the elbow on the same side. They were hard, freely movable, and nontender. A larger, almond-size nodule developed in the right cheek. This node was adherent to the epithelium and also nontender. The drainage from the hand and palate stopped during the ensuing 6 months. The ulcerations over the dorsum of the right hand healed well. Because of resistance to all therapy, the fifth toe and metatarsal bone were amputated. The wound healed well without functional loss. Further surgical excisions are contemplated. Biopsies of an epitrochlear lymph node and two subcutaneous nodules from the hand had been performed previously. These, as well as the ampntated specimen again showed granulomatous tissue, similar to that demonstrated on the early biopsy specimen of this patient (Fig. 5). There were in addition small areas of liquefaction. Acid-fast bacilli appeared to be present on a smear made from material of the subcutaneous nodules, but could not be cultured from this or the other biopsy specimen. Cultures for fungi, Nocardia, and other organisms were negative, except for the presence of a Staphylococcus aureus (phage type 52-80) in the amputated specimen of the draining foot lesion and the nodular skin lesions of the hand. CASE 2 D. B. was a 10-month-old Negro girl, who presented with a history of cold and fever of one week's duration. During this period the mother had noticed that the right foot was painful to touch. Prior to the onset of these symptoms, she had been in good health. Chickenpox and a measleslike rash were the only illnesses in the past. Physical examination. The infant was well developed and well nourished. She appeared toxic with a temperature of 103~ F. Respirations were 38, pulse 130 per minute. The retroauricular nodes were moderately enlarged and questionably tender. Moist rales were heard in the right upper chest, but there was no dullness to percussion. Auscultation of the heart was normal. Examination of the abdomen showed a reducible inguinal hernia, no organomegaly, and no masses. The tibia, just above the malleolus, appeared somewhat thickened and slightly tender to palpation, but there was no other evidence of acute infection. Laboratory findings. On admission, the hemoglobin was 7.2 Gin. per 100 ml. reticulocyte count 3 per cent. The sickle cell preparation was
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Atypical mycobacteria and chronic bone disease
negative. The red blood cell morphology was compatible with iron-deficiency anemia. The leukocyte count was 12,400 per cubic millimeter, with 72 per cent segmented and 4 per cent nonsegmented polymorphonuclear cells, 16 per cent lymphocytes, and 8 per cent monocytes. The sedimentation rate was 84 ram. at one hour. Urinalysis was negative. The results were normal for concentrations of serum electrolytes, urea nitrogen, calcium, phosphorus, and alkaline phosphatase. A throat culture produced coliform organisms and a-streptococci. The first blood culture produced a coagulase-negative Staphylococcus albus. Two subsequent blood cultures taken on the same day were negative. Skin tests with increasing dilutions of old tuberculin and a histoplasmin skin test were also negative. Radiologic examinations. An x-ray of the right foot, taken on admission, showed periosteal proliferation involving the lower one-third of the tibia. A mild degree of demineralization was present in that region. The chest x-ray on admission revealed increased hilar markings and segmental bronchopneumonia involving the superior and anteromedial segment of the left lower lobe. There appeared to be fluid in the major fissure on that side. One week later, the bronchopneumonie process had extended over 'the entire lung, giving a more patchy appearance (Fig. 8). X-rays of the right foot, taken 2 weeks after admission, showed periosteal new bone extending halfway up the tibial shaft. A radiolucent defect was noted in the lower third of the right tibia. Four weeks after admission the periosteal new bone showed a sharp cutoff at the edge of the lytic lesion suggestive of tumor or inflammatory tissue projecting beyond the bone (Fig. 9). Hospital course. O n admission, the patient was treated with penicillin and chloramphenicol for pneumonia and what was thought to be acute osteomyelitis. For the first 5 days the temperature was characteristic of a septic process. Following this, there was some improvement in the general condition of the child and the temperature became normal. The patient subsequently continued to have febrile episodes lasting from several days to 2 weeks. Rhinorrhea and a mild cough were present intermittently throughout the entire hospital stay with moist rales audible over the chest on several occasions. The leukocyte count was in the range of 14,000 to 16,000 per cubic millimeter with a normal differential. There was no change in the rather benign appearance of the right leg until one month after
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admission when the patient developed a localized, tender, slightly erythematous fluctuant swelling over the right lower tibia. The right inguinal lymph nodes at this time were enlarged. Aspiration of the small, fluctuating mass produced 2 ml. of pus. There was no growth on routine media. Three aspirations were performed subsequently, and very little fluid was obtained. One culture grew out /?-hemolytic streptococcus. Cultures for fungi were negative; cultures for acidfast organisms were not obtained. A tuberculin skin test performed 7 weeks after admission was negative. A questionably positive reaction was obtained one week later with old tuberculin
Fig. 8. Case 2. Chest x-ray, taken one week after admission, showing extension of bronchopneumonic process with patchy densities involving the entire lung.
Fig. 9. Case 9. X-ray of right foot, taken 4 weeks after admission, showing a radiolucent defect in the lower third of the right tibia, with periosteal proliferation extending halfway up the tibial shaft. The periosteal new bone shows a sharp cutoff at the edge of the lytic lesion suggestive of tumor or inflammatory tissue projecting beyond the bone.
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Krieger, Hahne, and Whitten
September 1964
(1:1,000). Repeated tests with old tuberculin (1 : 1,000 and 1 : 100) were positive. At this time, three gastric washings were performed, one of which was positive on smear for AFB. (The cultures reported 6 weeks later were "negative for Myeobacterium tuberculosis"). Because the conversion of the tuberculosis skin test and the positive gastric washing suggested that the bone and pulmonary lesions represented tuberculosis, the patient was transferred to a tuberculosis hospital. The chest x-ray upon transfer showed prominent hilar shadows. A soft tissue density in the right paratracheal region now looked more like a lymph node. Hazy irregular infihates were present along the left cardiac border. Nondescript densities in the remaining lung fields were described as "vascular markings"; they subsequently developed a nodular character. After one week of treatment with INH and PAS the temperature became normal and remained so throughout the entire hospital stay. A small sinus in the area previously aspirated drained for 3 weeks and persisted for several months. Secretions from this sinus were examined on six occasions, and AFB were seen on the smears of three specimens. Cultures of these three specimens produced slow-growing, catalasepositive acid-fast organisms, which were classified as scotochromogens. ~ Guinea pigs injected subcutaneously with the organism were sacrificed 6 weeks after inoculation and showed only suppurative lesions of the inguinal nodes. The first and fifth specimens, taken two weeks apart, grew out staphylococcus, coagulase positive. This was coincident with an ear infection producing a staphylococcus of the same phage type (83A). Three more gastric washings were performed. Two showed acid-fast rods on direct smears and grew out atypical mycobacteria, not further specified. Therapy with chloramphenicol and subsequently methicillin was continued for one month. Radiologic examinations showed that the right lung cleared within 3 months, while the nodular densities remained unchanged on the left. Two months later, calcific changes were evident as hard, ringlike densities in the left hilar region. Along the left heart border was a residual infiltrate. , Gastric washings were repeated four times at
intervals after antituberculosis therapy was begun and were negative. Skin tests for Mycobacterium tuberculosis and Group I - I I I atypical mycobacteria were performed and gave the following reactions, measured in millimeters of induration: PPD-S, 12 to 13 mm.; PPD-Y (fiom Mycobac~terium kansasii), 8 to 10 mm.; PPD-236 (Bridge), 6 to 7 mm.; and PPD-B (Battey strain), 5 to 6 mm. '~ The patient was placed in a short leg cast for 6 months. Periodic x-rays of the right tibia showed a gradual decrease in the size of the radiolucency. Ten months after the initial admission only a small area of faint decalcification was visible in the distal end of the right tibia. The lung had cleared 12 months after the initial admission, except for the presence of calcifie densities in the hilar area. The hilar nodes were still suspiciously prominent one year later, when the patient was discharged. She was clinically well at the last contact 2 months after discharge, at which time therapy with INH and PAS was still being continued.
qdentifieation through the Bacteriology Laboratories, Department of Health, Herman-Kiefer Hospital, Detroit, Mich.
~Supplied by Lydia Edwards, Department of Health, Education, and Welfare, Tuberculosis Program, Washington, D. C.
DISCUSSION T h e offending o r g a n i s m in these two cases is thought to be a scotochromogen. This organism belongs to a group of mycobacteria which formerly has been designated as atypical, yellow, n o n p a t h o g e n i c , nonclassified, saprophytic, chromogenic, or nontubercuIous acid-fast. These atypical acid-fast organisms are now classified in four groups 1 on the basis of cultural characteristics, a, 24-2~ i.e., photochromogenic ( G r o u p I ) , scotochromogenic ( G r o u p I I ) , nonphotochromogenic m y c o b a c t e r i a ( G r o u p I I I ) , a n d rapid growers ( G r o u p I V ) . Organisms belonging to the latter group have similarities with the N o c a r d i a species. Identification is most reliably established by the presence of chromogenicity in darkness or after exposure to light, by the absence of niacin production, a n d by the type of a n i m a l virulence. Atypical AFB are less virulent t h a n Mycobacterium tuberculosis in guinea pigs in that they fail to produce progressive, fatal disease; however, they do produce localized lesions at the injection site or in l y m p h nodes.
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In the attempt to characterize individual chromogenic infections it is difficult to use early case reports since they do not distinguish between the various groups of atypical AFB. Recent surveys seem to indicate that scotochromogens, while frequently the cause of lymphadenitis in children, ~2 rarely cause chronic lung disease. If demonstrated in lung lesions they are with few exceptions 1~ 12 associated with other organisms, particularly Mycobacterium tuberculosis, 1,1~ or else lung disease has preceded themS, 0 Photochromogens, on the contrary, are demonstrated with increasing frequency as the sole organism, and probably the causative organism, in chronic lung lesions. The involvement of distant structures, particularly bony ones, is rare for all types of atypical AFB. Wood 4 reported 4 cases of infection due to "yellow AFB" where at least one other organ system in addition to the lung was involved, i.e., genitourinary system, spleen, retina, and skin. To date, only 5 cases have been described in which atypical AFB were demonstrated in bone lesions. Weed's ~9 case had striking similarities with our Case 1. This patient was a 16-year-old boy who h a d multiple osseous lesions with sinus formation which recurred over a period of 10 years. Atypical AFB were the only organisms consistently found in all specimens and the only ones cultured from two closed lesions. Cure was accomplished by surgical excision of bone lesions. In a second case, 18 atypical AFB were demonstrated in a chronic granuloma removed from the scapula of a 16-year-old patient. In these 2 cases the organisms were chromogenic and hence similar to the organisms isolated from our patients. The remaining three cases with osseous involvement 2~ were associated with nonchromogenic mycobacteria or an organism possibly belonging to the Nocardia group. 2~ These 3 cases had several characteristics in common. The patients were all under the age of 3 years. In each there was widespread osseous involvement with granulomatous lesions cont'aining histiocytes and foam cells and the atypical AFB could be demonstrated intra-
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cellularly. None of the children recovered. Lunn 23 describes the case of a 5-year-old boy with skin ulcers, caused by "Mycobc~cterium ulcerans or a related organism," who also had metastatic necrotizing granulomas in bone. He cites other cases of pseudocystic bone disease, which were probably caused by mycobacteria other than Mycobacterium tuberculosis. However, in none of these cases was the organism demonstrated in the bone lesions. It is the impression of most observers that the symptoms and course of infections with chromogenic mycobacteria are, in general, more benign than in disease of equal extent caused by Mycobacterium tuberculosis. 4 This is especially evident in scotochromogenic lung infections. 1~ The persistence of cavitary lung disease due to scotochromogens in asymptomatic males who are able to continue heavy work is particularly striking. 12 A definite diagnosis calls for the repeated demonstration of the same atypical AFB from closed lesions. Although this criterion was not fulfilled in our cases, we feel that the clinical features and laboratory findings make the diagnosis of a chromogenic infection highly probable. Our patients had clinical features which appear to be characteristic of infections caused by atypical mycobacteria, i.e., paucity of symptoms, chronicity, and poor response to specific antituberculosis therapy. s-10. ~z, 18, 21 Scotochromogens appear t o be the most resistant of the four groups of atypical mycobacteria, The following laboratory findings support the diagnosis of a chromogenic infection in our patients. In Case 1 a chromogenic mycobacterium was demonstrated early in the course of the disease in a closed osseous lesion and an atypical niacin-negative AFB was found in one gastric washing. Scotochromogenic mycobacteria were subsequently identified in cultures from each of the draining sites in the mouth, hand, and foot, in two gastric washings, and AFB were seen on a smear of drainage material from the foot. Similarly, scotochromogenie mycobacteria were cultured in 3 of 6 specimens ob-
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Krieger, Hahne, and Whitten
tained from the draining wound in Case 2. Contamination cannot be ruled out with certainty. However, seotochromogens were repeatedly demonstrated at various sites and different times, while other microorganisms were not consistently found. The pyogenic organisms that were cultured are highly unlikely causes of chronic bone disease with sinus formation. Atypical AFB were present on several occasions in the gastric washings in both cases. The demonstration of atypical AFB in gastric washings can be taken only as circumstantial evidence since atypical mycobacteria have been found in saliva and gastric washings of healthy people 2~' 2s and less commonly in sputum. 29 Scotochromogens, in particular, are not significant when found inconsistently and in small numbers. In the present Case 2 atypical AFB were demonstrated repeatedly and in significant numbers in both smears and cultures of gastric washings. The fact that in this case gastric washings became negative upon recovery may be important. The two positive gastric washings in Case 1 are clearly related to the drainage from the mouth and nose. The incidence of positive gastric washings in normal individuals is variable, possibly due to procedural variations in individual laboratories, 29 but most of all influenced by geographical differences. Atypical AFB do not appear to be common in Michigan, where both patients had their continued residence from birth up to the time of hospitalization. Skin tests for Mycobacterium tuberculosis and atypical mycobacteria Groups I to I I I were positive in Case 2. The reports concerning skin sensitivity to standard testing material (old tuberculin and purified protein derivative) in patients with infections caused by atypical mycobacteria are numerous?' 9, 1~, 17, a0-ss There is sufficient evidence to indicate that cross-sensitivity is common. Differentiation of the various groups of mycobacteria by skin testing may therefore not be possible. We have no explanation for the fact that no skin sensitivity was shown by Patient N. B. (Case 1).
September 1964
Before atypical AFB r e c e i v e d general recognition as potential pathogens, it was suggested by Weed ~s that the organisms were opportunists which were carried in blood or lymph, causing disease only in a locus minoris resistentiae. It might well be argued that Case 1 represents a nontuberculous granulomatous disease with secondary infection by an atypical AFB. This case had some characteristics of sarcoidosis. A direct etiologic relationship between atypical AFB and sarcoidosis has been suggested by Chapman a4 who demonstrated antibodies to "anonymous" mycobacteria in 78 to 87.5 per cent of patients with sarcoidosis. The phenomenon cannot be fully explained, however. It was the disseminated nature of the granulomatous process and the radiologic appearance of the metacarpal and metatarsal lesions which were originally suggestive of sarcoidosis. The differential diagnosis between sarcoidosis of the metacarpal and metatarsal bones and tuberculous diaphysitis is difficult, s~ The diagnosis frequently remains uncertain even after biopsy in cases where caseous necrosis or acid-fast rods cannot be demonstrated. On biopsy, only small areas of liquefaction, surrounded by epithelioid and inflammatory cells, were seen; there was no typical caseation in this case. However, the presence of multiple draining sinuses is incompatible with the diagnosis of sarcoidosis. Underlying sarcoidosis with secondary implantation of a scotochromogenic mycobacterium cannot be ruled out. Such a mechanism has to be considered also in the above-mentioned three cases 2~ of fatal disseminated osteomyelitis in which nonchromogenic mycobacteria were found in lesions which apparently otherwise resembled diseases of the reticuloendothelial system.
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33. 34. 35.
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lomas, Proc. Staff Meet. Mayo Clin. 31: 246, 1956. Weed, L. A., Karlson, A. G., Ivins, J. "C., and Miller, R. H.: Recurring migratory osteomyelitis associated with saprophytic acidfast bacilli, Proc. Staff Meet. Mayo Clin. 31" 238, 1956. Cuttino, J. T., and McCabe, A. M.: Pure granulomatous nocardiosis: A new fungus disease distinguished by intraeelluIar parasitism, Am. J. Path. 25" 1, 1949. Van der Hoeven, L. H., Rutten, F. J., and Van der Sar, A.: An unusual acid-fast bacillus causing systemic disease and death in a child, Am. J. Clin. Path. 29" 433, 1958. Yakovac, W. C., Baker, R., Schweigert, C., and Hope, J. W.: Fatal disseminated osteomyelitis due to an anonymous mycobacterium, J. PEDIAT. 59: 909, 1961. Lunn, H. F.: MycobacteriaI lesions in bone, East African M. J. 40: 113, 1963. Huppert, M., Wayne, L. G., and Juarez, W. J.: Characterization of atypical mycobacteria and of Nocardia species isolated from clinical specimens, Am. Rev. Tuberc. 76: 468, 1957. Pollak, A., and Buhler, V. B.: The cultural characteristics and animal pathogenicity of an atypical acid-fast organism which causes human disease, Am. Rev. Tuberc. 71: 74, 1955. Tarshis, M. S., and Friseh, A. M.: Chromogenie acid-fast bacilli from human sources. I. Cultural characteristics, Am. Rev. Tuberc. 65: 278, 1952. Edwards, L. B., and Palmer, C. E.: Isolation of "atypical" mycobacteria from healthy persons, Am. Rev. Respiratory Dis. 80: 747, 1959. Atwell, R. J., and Pratt, P. C.: Unclassified mycobaeteria in the gastric contents of healthy persons and of patients of a tuberculosis hospital, Am. Rev. Respiratory Dis. 81" 888, 1960. Runyon, E. H.: Source of scotochromogens, Am. Rev. Respiratory Dis. 80: 277, 1959. Mellman, W. J., and Barness, L. A.: Unclassified mycobacteria and tuberculin reactions, A. M. A. J. Dis. Child. 104: 21, 1962. Kendig, E. J., Jr.: Unclassified mycobaeteria in children, presented at 71st Annual Meeting, American Pediatric Society, May 2 and 3, 1961. Palmer, C. E.: Tuberculin sensitivity and contact with tuberculosis, further evidence of nonspecific sensitivity, Am. Rev. Tuberc. 68: 678, 1953. Edwards, L. B., and Palmer, C. E.: Epidemiologic studies of tuberculin sensitivity, Am. J. Hyg. 68: 213, 1958. Chapman, J. S.: Myeobacterial and mycotic antibodies in sera of patients with sareoidosis, Ann. Int. Med. 55: 918, 1961. Caffey, J.: Pediatric x-ray diagnosis, 1961, ed. 4, Year Book Medical Publishers, Inc.
September 1964
T h e J o u r n a l of P E D I A T R I C S
A typical myco bacteria as a probable cause of chronic bone disease A report oJ two cases
Two cases o[ chronic and apparently inflammatory bone and lung disease are presented in which the offending organisms are thought to be atypical mycobacteria. Scotochromogens were found in smears and cultures of material obtained from the bone lesions and gastric washings. The patients had features which appear to be characteristic of infections due to atypical mycobacteria, i.e., paucity of symptoms, poor response to antituberculosis therapy, and chronicity. The two cases strongly suggest that these organisms have the ability to cause bone disease. It is felt that awareness of this possibility will probalby uncover other cases in which the demonstration of "yellow" acid-fast bacilli would otherwise be attributed to accidental contamination.
Ingeborg Krieger, M.D.,* Otto H. Hahne, M.D., and Charles F. Whitten, M.D. DETROIT~ M I C H .
I N R E C E N T years m u c h attention has been focused on a group of atypical acid-fast bacilli (AFB), the photochromogenic, scotochromogenic, nonphotochromogenic mycobacteria, and rapid growers? These acid-fast organisms were formerly considered to be nonpathogenic. Evidence from cases of chronic pulmonary disease strongly suggests that atypical AFB are potentially pathogenic, for they have been present consistently in sputum or else have been the sole microor-
From the Pediatric Department of Detroit Receiving Hospital and the Herman Kie[er Hospital, Tuberculosis Division. "~Address, Wayne State Unlversity School of Medicine, c/o Children's Hospital of Michigan, 5224 St. Antoine St., Detroit 2, Mich.
ganism in resected lung specimens. 1-12 Furthermore, the occurrence of cervical adenitis due to these organisms is now well documented. 12-17 Apparently, only 5 cases have been reported in which atypical AFB were found in specimens obtained from bone lesions? s-22 Three patients h a d fatal systemic disease associated with disseminated osteomyelitis due to a nonchromogenic AFB 21, 22 or an organism possibly belonging to the Nocardia groupY ~ Since so few observations have been made relative to the possibility of an association between bone disease and atypical mycobacteria, the following two cases are reported. T h e features c o m m o n to these cases are: chronic osteomyelitis, chronic lung
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disease, a n d the presence of a scotochromogen in gastric washings a n d in smears a n d cultures of m a t e r i a l o b t a i n e d from the bone lesions. CASE 1 N. B. was a 5-year-old Negro boy who presented with swelling of the dorsum of the right hand for 2 months and of the left foot for 3 weeks. Physical findings. The physical examination revealed a well-developed, well-nourished boy in apparent good health. Temperature, pulse, and respiration were normal. A firm, indurated, nontender swelling was felt over the ulnar aspect of the dorsum of the right hand. A similar swelling was present dorsolaterally over the left metatarsal area. There was mild generalized lymphadenopathy with marked enlargement of the left inguinal and right epitrochlear nodes. The remainder of the physical examination, ineluding a complete ophthalmologic examination, was negative. Laboratory findings. On admission, the hemoglobin was 11.6 Gm. per cent. The red blood cell count was 4.26 million per cubic millimeter; reticulocyte count, 1.4 per cent; leukocyte count, 4,900 per cubic millimeter with 58 per cent polymorphonuclear neutrophils, 29 per cent lymphocytes, and 13 per cent eosinophils. The bone marrow showed an acceleration of myeloid leukogenesis which was not diagnostic. The urinalysis was negative. The serum glucose, urea nitrogen, total protein, albumin/globulin ratio, caIcium, phosphorus, and alkaline phosphatase Were normal. Tests for heterophil and febrile agglutinins and the Kline test were negative, as were skin tests for blastomycosis, histoplasmosis, and coccidioidomycosis. Skin tests with old tuberculin (1 : 1,000 and 1: 100) were negative. Radlologic examinations. Roentgenograms of the chest taken on admission and one week later showed diffuse perihilar densities (Fig. 1) and an area of increased density in the left lower lobe. A bone survey, taken on admission, showed a large medullary defect in the fourth right metacarpal diaphysis with expansion of this portion of bone, but absence of periosteal reaction. The proximal diaphysis was affected to a lesser degree. The radial diaphysis showed an illdefined lucent area occupying the posterior and medial portion of the medullary canal next to the cortex. There was expansion of bone at this
34 1
point, but no cortical destruction or periosteal reaction (Fig. 2). X-rays of the left foot showed cortical destruction and expansion of the fifth metatarsal bone without periosteal reaction (Figs. 3 and 4). The remainder of the bone survey was negative. Further studies. On the fifth hospital day a right axillary lymph node was removed for biopsy and showed noncaseating granulomatous tissue, with epithelioid ceils and a few giant cells. On the tenth hospital day biopsies of the metacarpal and metatarsal lesions were performed. These revealed numerous noncaseating granulomas with replacement of bone in some areas (Fig. 5). The histopathologic appearance of the lymph node, metacarpal and metatarsal lesions was compatible with the diagnosis of sarcoidosis. Although no acid-fast bacteria were detected in the sectioned material, a smear of the biopsy materiaI obtained from the metacarpal lesion did reveal acid-fast organisms. (The smear from the metatarsal lesion was negative.) Unfortunately, this report did not come immediately to the attention of the medical staff. The anaerobic culture grew out micrococci and the aerobic culture coagulase-negative Staphylococcus albus and a-streptococci. Hospital course. A presumptive diagnosis of sarcoidosis was made and the child was treated with steroids for 2 months. In addition erythromycin was given for a short time postoperatively. His hospital course was uncomplicated except for development of moon facies and occasional temperature spikes to 101 ~ F. The operative wounds healed well but the metacarpal and metatarsal swellings persisted, Two and one-hail months after admission the culture of material from the metacarpal lesion
Fig. 1. Case 1. Chest x-ray, taken on admission, showing densities in the perihilar region and left lower lobe.
3 42
Krieger, Hahne, and Whitten
Fig. 2. Case 1. X-ray of the right hand showing medullary defects and expansion of bone, most prominent in the distal portion of the fourth metacarpal diaphysis. Ill-defined lucent area in the posterior and medial portion of the radial diaphysis, adjacent to the cortex, which is intact. Minimal expansion of bone at this point. No periosteal reaction present at either site.
Figs. 3 and 4. Case 1. X-rays of the left foot, taken on admission, showing cortical destruction and expansion of the fifth metatarsal bone without periosteal reaction. showed a "TB-like organism growing in smooth, wet appearing colonies." In the inoculated guinea pig it produced localized le~ions around the injection site, but no progressive disease. The organism was classified as a nonvirulent chromogen (niacin negative, catalase actively positive).* The cultures obtained from the metatarsal lesion and *Identification through the Bacteriology Laboratories, Department of Health, Herman-Kiefer Hospital, Detroit, Mieh.
September 1964
the initial gastric washing did not grow out organisms. X-rays taken at this time showed a small patch of density remaining in the left lower lobe adjacent to the diaphragm. Roentgenograms of the involved bones showed a slight decrease in the size of the previously described radiolucencies. Sclerosis, evidenced by increasing densities in areas surrounding the lytic defect, was present in both the metacarpal and metatarsal lesion. In view of the culture report, which suggested an etiologic relationship with an acid-fast organism, two and one-half months after admission the patient was transferred to a tuberculosis sanatorium and given isoniazid ( I N H ) , 350 mg., and para-amino salicylic acid (PAS), 3.5 Gm. per day. Laboratory tests remained essentially normal, except for mild, persistent eosinophilia of 3 to 6 per cent. Skin tests with old tuberculin (1:1,000 and 1:100) and with the purified protein derivate (0.0001) were repeated on several occasions and were consistently negative. Ten months after the original admission, signs of an acute inflammation of the left foot developed. Pus draining from the left foot was cultured and produced a hemolytic Micrococcus pyogenes var. aureus and Gaffkya tetragena. Only one culture for acid-fast organisms was performed on the drainage material and it was negative. Cultures of one of the two gastric washings performed at this time revealed atypical, niacinnegative AFB. The patient was treated with bed rest and wet compresses. Antituberculosis therapy was continued and no antibiotics were given. The sinus closed within 3 weeks but subsequently reopened and drained intermittently. Exactly one year after the original admission, x-rays of the chest revealed a persistent parenchymal infiltrate in the basilar region on the left (Fig. 6). The right radius showed a persistent, though less pronounced, radiolucent defect. The fourth right metacarpal and fifth left metatarsal bones revealed sclerotic lesions with spotty radiolucencies, prominent trabecular pattern, and intact cortical margins. The one gastric washing performed at this time was negative for AFB. The patient was discharged and one month later all therapy was discontinued. Seven months after discharge a swelling was first noted over the lateral aspect of the dorsmn of the right hand. The patient's general condition was good, and there was no local tenderness. An x-ray of the hand showed no change in the appearance of the bone lesion. Antituberculosis therapy ( I N H and PAS) was reinstituted
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343
Fig. 5. Case 1. Representative section of granulomatous tissue (metacarpal lesion). Poorly defined granuloma, fairly well vascularized, composed almost exclusively of epithelioid cells and inflammatory ceils. Absence of caseation necrosis. Mutinucleated giant cells were sparse, poorly formed, with rarely more than three nuclei present in one plane.
on an ambulatory basis. A few months later, i.e., approximately 2 years from the onset of the original illness, the mother noted an indolent swelling to the right of the bridge of the nose, which increased in size, while the patient was apparently still under antituberculosis therapy. Subsequently the foot started draining again, a draining sinus formed over the original lesion in the right hand, and the facial lesion broke through the hard palate. The patient, who had temporarily been lost to follow-up care, was finally readmitted to the sanatorium. The physical examination showed persistent, generalized lymphadenopathy. The epitrochlear nodes were palpable on both sides. Physical findings were otherwise limited to the three areas of osseous involvement in the hand, foot, and face. Inflammatory signs were mild; the swellings of the hand and foot were plum size, hard, and nontender. There was a hard, almond-size protuberance medial and inferior to the inferior orbital ridge. The hard palate was ulcerated, showing a midline oval sinus opening with granulated edges. Drainage from the three sites was intermittent and minimal. Material from these three draining lesions was examined for AFB on smear and culture four times each within the ensuing six months. Scotochromogens *
were cultured from the hand, foot, and palate each in one of these four specimens. Acid-fast bacilli were also demonstrated on a smear of drainage material from the foot. The scotochromogens were resistant to I N H , PAS, streptomycin,
~Identification through the Bacteriology Laboratories, Department of Health, Herman-Kiefer Hospital, Detroit, Mich.
Fig. 6. Case 1. Lateral chest x-ray, taken one year after admission, showing persistent parenchymal infiltrate in the basilar region on the left.
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Krieger, Hahne, and Whitten
Fig. 7. Case 1. Photograph of the right hand showing the ulcerative lesion with chronic draining sinus and surrounding skin nodules. viomycin, ethionamide, cycloserine, kanamycin, and pyrazinamide. Cultures for fungi were negative. A Staphylococcus aureus (phage type 5280) was cultured twice from the draining lesion of the hand. The material from the lesion of the hand was negative on dark-field examination for spirochetes. Eight gastric washings were performed. Scotochromogens were cultured in 2 of the washings at a time when the draining sinus in the hard palate showed the same organism. Radiologic examination of the fourth right metacarpal and fifth left metatarsal bones showed no significant change. There was expansion of bone with numerous spotty radiolucencies. A latteral view of the skull showed a foamy-appearing bone lesion with a thin outer shell protruding from the anterior wall of the maxillary antrum, which was itself thickened and contained minute radiolucencies. A new area of radiolucency was discovered in the distal portion of the left humerus, which was similar to that seen originally in the right radial diaphysis in that the cortex was intact. The previously lucent area in the right radius showed sclerosis and some cortical thickening. Skin tests for Group I - I I I atypical mycobacteria "x were negative. Skin tests for the following diseases were repeated a n d again negative: histoplasmosis, coccidioidomycosis, blastomycosis, and brucellosis. Serum concentrations of immune globulins were normal. Antituberculosis therapy was continued as before. Streptomycin was added, but discontinued after a period of 3 months. The patient subsequently developed eight small subcutaneous nodules, four in the area of the draining hand *Supplied by Lydia Edwards, Department of Health, Education, and Welfare, Tuberculosis Program, Washington, D.C.
September 1964
lesion (Fig. 7) and four in the region of the elbow on the same side. They were hard, freely movable, and nontender. A larger, almond-size nodule developed in the right cheek. This node was adherent to the epithelium and also nontender. The drainage from the hand and palate stopped during the ensuing 6 months. The ulcerations over the dorsum of the right hand healed well. Because of resistance to all therapy, the fifth toe and metatarsal bone were amputated. The wound healed well without functional loss. Further surgical excisions are contemplated. Biopsies of an epitrochlear lymph node and two subcutaneous nodules from the hand had been performed previously. These, as well as the ampntated specimen again showed granulomatous tissue, similar to that demonstrated on the early biopsy specimen of this patient (Fig. 5). There were in addition small areas of liquefaction. Acid-fast bacilli appeared to be present on a smear made from material of the subcutaneous nodules, but could not be cultured from this or the other biopsy specimen. Cultures for fungi, Nocardia, and other organisms were negative, except for the presence of a Staphylococcus aureus (phage type 52-80) in the amputated specimen of the draining foot lesion and the nodular skin lesions of the hand. CASE 2 D. B. was a 10-month-old Negro girl, who presented with a history of cold and fever of one week's duration. During this period the mother had noticed that the right foot was painful to touch. Prior to the onset of these symptoms, she had been in good health. Chickenpox and a measleslike rash were the only illnesses in the past. Physical examination. The infant was well developed and well nourished. She appeared toxic with a temperature of 103~ F. Respirations were 38, pulse 130 per minute. The retroauricular nodes were moderately enlarged and questionably tender. Moist rales were heard in the right upper chest, but there was no dullness to percussion. Auscultation of the heart was normal. Examination of the abdomen showed a reducible inguinal hernia, no organomegaly, and no masses. The tibia, just above the malleolus, appeared somewhat thickened and slightly tender to palpation, but there was no other evidence of acute infection. Laboratory findings. On admission, the hemoglobin was 7.2 Gin. per 100 ml. reticulocyte count 3 per cent. The sickle cell preparation was
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Atypical mycobacteria and chronic bone disease
negative. The red blood cell morphology was compatible with iron-deficiency anemia. The leukocyte count was 12,400 per cubic millimeter, with 72 per cent segmented and 4 per cent nonsegmented polymorphonuclear cells, 16 per cent lymphocytes, and 8 per cent monocytes. The sedimentation rate was 84 ram. at one hour. Urinalysis was negative. The results were normal for concentrations of serum electrolytes, urea nitrogen, calcium, phosphorus, and alkaline phosphatase. A throat culture produced coliform organisms and a-streptococci. The first blood culture produced a coagulase-negative Staphylococcus albus. Two subsequent blood cultures taken on the same day were negative. Skin tests with increasing dilutions of old tuberculin and a histoplasmin skin test were also negative. Radiologic examinations. An x-ray of the right foot, taken on admission, showed periosteal proliferation involving the lower one-third of the tibia. A mild degree of demineralization was present in that region. The chest x-ray on admission revealed increased hilar markings and segmental bronchopneumonia involving the superior and anteromedial segment of the left lower lobe. There appeared to be fluid in the major fissure on that side. One week later, the bronchopneumonie process had extended over 'the entire lung, giving a more patchy appearance (Fig. 8). X-rays of the right foot, taken 2 weeks after admission, showed periosteal new bone extending halfway up the tibial shaft. A radiolucent defect was noted in the lower third of the right tibia. Four weeks after admission the periosteal new bone showed a sharp cutoff at the edge of the lytic lesion suggestive of tumor or inflammatory tissue projecting beyond the bone (Fig. 9). Hospital course. O n admission, the patient was treated with penicillin and chloramphenicol for pneumonia and what was thought to be acute osteomyelitis. For the first 5 days the temperature was characteristic of a septic process. Following this, there was some improvement in the general condition of the child and the temperature became normal. The patient subsequently continued to have febrile episodes lasting from several days to 2 weeks. Rhinorrhea and a mild cough were present intermittently throughout the entire hospital stay with moist rales audible over the chest on several occasions. The leukocyte count was in the range of 14,000 to 16,000 per cubic millimeter with a normal differential. There was no change in the rather benign appearance of the right leg until one month after
345
admission when the patient developed a localized, tender, slightly erythematous fluctuant swelling over the right lower tibia. The right inguinal lymph nodes at this time were enlarged. Aspiration of the small, fluctuating mass produced 2 ml. of pus. There was no growth on routine media. Three aspirations were performed subsequently, and very little fluid was obtained. One culture grew out /?-hemolytic streptococcus. Cultures for fungi were negative; cultures for acidfast organisms were not obtained. A tuberculin skin test performed 7 weeks after admission was negative. A questionably positive reaction was obtained one week later with old tuberculin
Fig. 8. Case 2. Chest x-ray, taken one week after admission, showing extension of bronchopneumonic process with patchy densities involving the entire lung.
Fig. 9. Case 9. X-ray of right foot, taken 4 weeks after admission, showing a radiolucent defect in the lower third of the right tibia, with periosteal proliferation extending halfway up the tibial shaft. The periosteal new bone shows a sharp cutoff at the edge of the lytic lesion suggestive of tumor or inflammatory tissue projecting beyond the bone.
3 46
Krieger, Hahne, and Whitten
September 1964
(1:1,000). Repeated tests with old tuberculin (1 : 1,000 and 1 : 100) were positive. At this time, three gastric washings were performed, one of which was positive on smear for AFB. (The cultures reported 6 weeks later were "negative for Myeobacterium tuberculosis"). Because the conversion of the tuberculosis skin test and the positive gastric washing suggested that the bone and pulmonary lesions represented tuberculosis, the patient was transferred to a tuberculosis hospital. The chest x-ray upon transfer showed prominent hilar shadows. A soft tissue density in the right paratracheal region now looked more like a lymph node. Hazy irregular infihates were present along the left cardiac border. Nondescript densities in the remaining lung fields were described as "vascular markings"; they subsequently developed a nodular character. After one week of treatment with INH and PAS the temperature became normal and remained so throughout the entire hospital stay. A small sinus in the area previously aspirated drained for 3 weeks and persisted for several months. Secretions from this sinus were examined on six occasions, and AFB were seen on the smears of three specimens. Cultures of these three specimens produced slow-growing, catalasepositive acid-fast organisms, which were classified as scotochromogens. ~ Guinea pigs injected subcutaneously with the organism were sacrificed 6 weeks after inoculation and showed only suppurative lesions of the inguinal nodes. The first and fifth specimens, taken two weeks apart, grew out staphylococcus, coagulase positive. This was coincident with an ear infection producing a staphylococcus of the same phage type (83A). Three more gastric washings were performed. Two showed acid-fast rods on direct smears and grew out atypical mycobacteria, not further specified. Therapy with chloramphenicol and subsequently methicillin was continued for one month. Radiologic examinations showed that the right lung cleared within 3 months, while the nodular densities remained unchanged on the left. Two months later, calcific changes were evident as hard, ringlike densities in the left hilar region. Along the left heart border was a residual infiltrate. , Gastric washings were repeated four times at
intervals after antituberculosis therapy was begun and were negative. Skin tests for Mycobacterium tuberculosis and Group I - I I I atypical mycobacteria were performed and gave the following reactions, measured in millimeters of induration: PPD-S, 12 to 13 mm.; PPD-Y (fiom Mycobac~terium kansasii), 8 to 10 mm.; PPD-236 (Bridge), 6 to 7 mm.; and PPD-B (Battey strain), 5 to 6 mm. '~ The patient was placed in a short leg cast for 6 months. Periodic x-rays of the right tibia showed a gradual decrease in the size of the radiolucency. Ten months after the initial admission only a small area of faint decalcification was visible in the distal end of the right tibia. The lung had cleared 12 months after the initial admission, except for the presence of calcifie densities in the hilar area. The hilar nodes were still suspiciously prominent one year later, when the patient was discharged. She was clinically well at the last contact 2 months after discharge, at which time therapy with INH and PAS was still being continued.
qdentifieation through the Bacteriology Laboratories, Department of Health, Herman-Kiefer Hospital, Detroit, Mich.
~Supplied by Lydia Edwards, Department of Health, Education, and Welfare, Tuberculosis Program, Washington, D. C.
DISCUSSION T h e offending o r g a n i s m in these two cases is thought to be a scotochromogen. This organism belongs to a group of mycobacteria which formerly has been designated as atypical, yellow, n o n p a t h o g e n i c , nonclassified, saprophytic, chromogenic, or nontubercuIous acid-fast. These atypical acid-fast organisms are now classified in four groups 1 on the basis of cultural characteristics, a, 24-2~ i.e., photochromogenic ( G r o u p I ) , scotochromogenic ( G r o u p I I ) , nonphotochromogenic m y c o b a c t e r i a ( G r o u p I I I ) , a n d rapid growers ( G r o u p I V ) . Organisms belonging to the latter group have similarities with the N o c a r d i a species. Identification is most reliably established by the presence of chromogenicity in darkness or after exposure to light, by the absence of niacin production, a n d by the type of a n i m a l virulence. Atypical AFB are less virulent t h a n Mycobacterium tuberculosis in guinea pigs in that they fail to produce progressive, fatal disease; however, they do produce localized lesions at the injection site or in l y m p h nodes.
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Atypical mycobacteria and chronic bone disease
In the attempt to characterize individual chromogenic infections it is difficult to use early case reports since they do not distinguish between the various groups of atypical AFB. Recent surveys seem to indicate that scotochromogens, while frequently the cause of lymphadenitis in children, ~2 rarely cause chronic lung disease. If demonstrated in lung lesions they are with few exceptions 1~ 12 associated with other organisms, particularly Mycobacterium tuberculosis, 1,1~ or else lung disease has preceded themS, 0 Photochromogens, on the contrary, are demonstrated with increasing frequency as the sole organism, and probably the causative organism, in chronic lung lesions. The involvement of distant structures, particularly bony ones, is rare for all types of atypical AFB. Wood 4 reported 4 cases of infection due to "yellow AFB" where at least one other organ system in addition to the lung was involved, i.e., genitourinary system, spleen, retina, and skin. To date, only 5 cases have been described in which atypical AFB were demonstrated in bone lesions. Weed's ~9 case had striking similarities with our Case 1. This patient was a 16-year-old boy who h a d multiple osseous lesions with sinus formation which recurred over a period of 10 years. Atypical AFB were the only organisms consistently found in all specimens and the only ones cultured from two closed lesions. Cure was accomplished by surgical excision of bone lesions. In a second case, 18 atypical AFB were demonstrated in a chronic granuloma removed from the scapula of a 16-year-old patient. In these 2 cases the organisms were chromogenic and hence similar to the organisms isolated from our patients. The remaining three cases with osseous involvement 2~ were associated with nonchromogenic mycobacteria or an organism possibly belonging to the Nocardia group. 2~ These 3 cases had several characteristics in common. The patients were all under the age of 3 years. In each there was widespread osseous involvement with granulomatous lesions cont'aining histiocytes and foam cells and the atypical AFB could be demonstrated intra-
34 7
cellularly. None of the children recovered. Lunn 23 describes the case of a 5-year-old boy with skin ulcers, caused by "Mycobc~cterium ulcerans or a related organism," who also had metastatic necrotizing granulomas in bone. He cites other cases of pseudocystic bone disease, which were probably caused by mycobacteria other than Mycobacterium tuberculosis. However, in none of these cases was the organism demonstrated in the bone lesions. It is the impression of most observers that the symptoms and course of infections with chromogenic mycobacteria are, in general, more benign than in disease of equal extent caused by Mycobacterium tuberculosis. 4 This is especially evident in scotochromogenic lung infections. 1~ The persistence of cavitary lung disease due to scotochromogens in asymptomatic males who are able to continue heavy work is particularly striking. 12 A definite diagnosis calls for the repeated demonstration of the same atypical AFB from closed lesions. Although this criterion was not fulfilled in our cases, we feel that the clinical features and laboratory findings make the diagnosis of a chromogenic infection highly probable. Our patients had clinical features which appear to be characteristic of infections caused by atypical mycobacteria, i.e., paucity of symptoms, chronicity, and poor response to specific antituberculosis therapy. s-10. ~z, 18, 21 Scotochromogens appear t o be the most resistant of the four groups of atypical mycobacteria, The following laboratory findings support the diagnosis of a chromogenic infection in our patients. In Case 1 a chromogenic mycobacterium was demonstrated early in the course of the disease in a closed osseous lesion and an atypical niacin-negative AFB was found in one gastric washing. Scotochromogenic mycobacteria were subsequently identified in cultures from each of the draining sites in the mouth, hand, and foot, in two gastric washings, and AFB were seen on a smear of drainage material from the foot. Similarly, scotochromogenie mycobacteria were cultured in 3 of 6 specimens ob-
3 48
Krieger, Hahne, and Whitten
tained from the draining wound in Case 2. Contamination cannot be ruled out with certainty. However, seotochromogens were repeatedly demonstrated at various sites and different times, while other microorganisms were not consistently found. The pyogenic organisms that were cultured are highly unlikely causes of chronic bone disease with sinus formation. Atypical AFB were present on several occasions in the gastric washings in both cases. The demonstration of atypical AFB in gastric washings can be taken only as circumstantial evidence since atypical mycobacteria have been found in saliva and gastric washings of healthy people 2~' 2s and less commonly in sputum. 29 Scotochromogens, in particular, are not significant when found inconsistently and in small numbers. In the present Case 2 atypical AFB were demonstrated repeatedly and in significant numbers in both smears and cultures of gastric washings. The fact that in this case gastric washings became negative upon recovery may be important. The two positive gastric washings in Case 1 are clearly related to the drainage from the mouth and nose. The incidence of positive gastric washings in normal individuals is variable, possibly due to procedural variations in individual laboratories, 29 but most of all influenced by geographical differences. Atypical AFB do not appear to be common in Michigan, where both patients had their continued residence from birth up to the time of hospitalization. Skin tests for Mycobacterium tuberculosis and atypical mycobacteria Groups I to I I I were positive in Case 2. The reports concerning skin sensitivity to standard testing material (old tuberculin and purified protein derivative) in patients with infections caused by atypical mycobacteria are numerous?' 9, 1~, 17, a0-ss There is sufficient evidence to indicate that cross-sensitivity is common. Differentiation of the various groups of mycobacteria by skin testing may therefore not be possible. We have no explanation for the fact that no skin sensitivity was shown by Patient N. B. (Case 1).
September 1964
Before atypical AFB r e c e i v e d general recognition as potential pathogens, it was suggested by Weed ~s that the organisms were opportunists which were carried in blood or lymph, causing disease only in a locus minoris resistentiae. It might well be argued that Case 1 represents a nontuberculous granulomatous disease with secondary infection by an atypical AFB. This case had some characteristics of sarcoidosis. A direct etiologic relationship between atypical AFB and sarcoidosis has been suggested by Chapman a4 who demonstrated antibodies to "anonymous" mycobacteria in 78 to 87.5 per cent of patients with sarcoidosis. The phenomenon cannot be fully explained, however. It was the disseminated nature of the granulomatous process and the radiologic appearance of the metacarpal and metatarsal lesions which were originally suggestive of sarcoidosis. The differential diagnosis between sarcoidosis of the metacarpal and metatarsal bones and tuberculous diaphysitis is difficult, s~ The diagnosis frequently remains uncertain even after biopsy in cases where caseous necrosis or acid-fast rods cannot be demonstrated. On biopsy, only small areas of liquefaction, surrounded by epithelioid and inflammatory cells, were seen; there was no typical caseation in this case. However, the presence of multiple draining sinuses is incompatible with the diagnosis of sarcoidosis. Underlying sarcoidosis with secondary implantation of a scotochromogenic mycobacterium cannot be ruled out. Such a mechanism has to be considered also in the above-mentioned three cases 2~ of fatal disseminated osteomyelitis in which nonchromogenic mycobacteria were found in lesions which apparently otherwise resembled diseases of the reticuloendothelial system.
REFERENCES
1. Runyon, E. H.: Anonymous mycobacteria in pulmonary disease, M. Clin. NOrth America 43: 273, 1959. 2. Florence, H.: Atypical acid-fast (chromo-
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3. 4.
5. 6.
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8.
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15. 16.
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Atypical mycobacteria and chronic bone disease
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