CASE REPORTS
Lepromatous Leprosy Masquerading As Disseminated Tuberculosis
IA(:K
B. WEISSMAN,
HAROLD
M.D.
C. NEU. M.D.
NI:IVYork, New York
A patient with disseminated leprosy is described. A 57 year old man from Cuba presented with fever and pancytopenia. Bone marrow aspirate showed numerous acid-fast bacilli and a liver biopsy specimen contained multiple granulomas. The patient was considered to have tuberculosis and was treated with isoniazid and rifampin, with initial clinical improvement, only to have the fever recur and to show deterioration in hematologic and hepatic function. Failure to grow M. tuberculosis suggested a diagnosis of leprosy which was proved by skin biopsy. How lepromatous leprosy can masquerade as disseminated tuberculosis is discussed. The protean manifestations, chronic course and infrequent occurrence of leprosy in the [Jnited States contribute to difficulties in early rccognition and diagnosis of this disease. Since leprosy is endemic in man! Caribbean countries, it is likely that urban centers with large immigrant communities harbor many patients with the disease. Leprosy may bc unrecognized either because it is not considered in the differential diagnosis or because it “masquerades” as another disease. The cutaneous manifestations of leprosy have been confused with systemic lupus erythematosus, psoriasis, erythema multiforme and cutaneous allergies [I]; the ncurologic manifestations have been confused with syringomyelia; the systemic manifestations with rheumatoid arthritis [2,3], polyarteritis nodosa [1,4], glomerulonephritis [4] and septicemia [1,4.5]. In most situations, definitive diagnosis becomes apparent when ;I biopsy specimen of appropriate material discloses acid-fast bacilli and the typical pathology. We describe here a patient in whom the diagnosis of leprosy was delayed, despite coml)atible biopsy material, 1~ca1~ of the similarity to disseminated tuberculosis. CASE REPORT A 57 year old construction Mcclical years
From the Department of Medicine, Division of Infectious Diseases. College of Physicians and Surgeons, Columbia Ilniversity and Medical Service, Presbyterian Hospital. New York, New York. Requests for reprints should bc addressed to Dr. Harold C. Neu. 630 West 168 Street, New York. New York 10032. Manuscript accepted N(,vcmbcr 8, 11f78.
Center
earlier
because
to the United
worker
was admitted
of fever States
and shaking from Cuba.
to the Columl)i;l-~‘rcsl,~t~~ri~lrl chills.
Hc hatI c,migr;ltctl
Hc had txxn
tight
well until twoyc;trs
prior to admission when erythcm;ltous. pruritic plaq~~cs clcvcl~~~~ctl (III his trunk and arms that rcsolvcd after scvcrol weeks of topical thcr;lpy. ‘I’cn ;lays IIcforc admission he noted malaise and Icthargy which, five days I;ltc:r. wcrc follo~~t:d by fever with temperatures to 4VC. shaking chills and antrrcuia. Hc had no cough, hemoptysis, chest pain, weight loss or headache. On admission the patient’s tcmpcraturc was 40”C, the bloocl lxcssrlrc SO/GO mm Hg, the pulse rate 130/min and thready. A faint c:rythorn,~tcnls mac111a1. crrlption was present. His livc:r was enlarged to 1-t cm in spn. but the: spleen was not palpable and thcrc w:fs no Iyml,h~ldanoi,ath\‘.
July 1979
The American
Journal
of Medicine
Volume
67
113
DISSEMINATED
LEPROMATOUS
LEPROSY-WEISSMAN,
NEU
Figure 1. Multiple granulomas as illustrated between the arrows with caseating necrosis and Langhans’ giant cells.
The white blood cell count was 3,500/mm3 with 77 per cent neutrophils of which 13 were band forms. The hematocrit value was 33 per cent. The erythrocyte sedimentation rate was 90 mm/hour (Westergren). The urea nitrogen was 8 mg/dl; the serum electrolytes and clotting profile were within the normal range of values. His total protein was 5.2 g/d1 of which 2.5 g/d1 was albumin. The alkaline phosphatase was 69 U. the serum glutamic oxaloacetic transaminase (SGOT) 39 LJ, the lactic dehydrogenase (LDH) 183 U and the bilirubin 0.5 mg/dl. A lumbar puncture was within normal limits. An x-ray film of the chest showed diffuse, mild peripheral interstitial scarring suggestive of chronic interstitial pulmonary disease. A specimen of arterial blood, drawn with the patient breathing room air, showed a pH of 7.51, a oxygen tension (~0~) of 87 mm Hg, and a carbon dioxide tension (pC0~) of 31 mm Hg. Multiple blood cultures were negative, as were cultures of urine and cerebrospinal fluid. Therapy with ampicillin and gentamicin was initiated since sepsis was suspected. The white blood cell count fell to 2,300/mm3 and the hematocrit value fell to 26 per cent with normochromic, normocytic indices. The platelet count declined to 9O,OOO/mms. Although the patient’s fever persisted, when cultures were negative antibiotics therapy was discontinued. The bilirubin level rose to 2.8 mg/dl, the SGOT to 70 U and the alkaline phosphatase to 146 U. A bone marrow aspirate on the fifth hospital day showed numerous acid-fast bacilli, and a diagnosis of disseminated tuberculosis was made. Therapy with isoniazid (300 mg daily] and rifampin (600 mg daily) was initiated. Fever, leukopenia and abnormal liver function tests persisted: a percutaneous liver biopsy specimen obtained after one week of antituberculous chemotherapy showed multiple granulomas (Figure 1). The patient became afebrile over the following week and remained afebrile after 14 days of therapy
114
July 1979
The American Journal of Medicine
with isoniazid and rifampin. His SGOT and LDH values became normal by the 21st hospital day. The patient was readmitted two weeks after discharge because of recurrence of fever, nausea and anorexia. The liver was now 11 cm in span and the spleen was palpable 3 cm below the costal margin. The hematocrit value was 26 per cent, the white blood cell count 4,000/mm3 and the sedimentation rate 150 mm/hour. A chest film again showed diffuse interstitial infiltrates. The bilirubin was 1.5 mg/dl, the alkaline phosphatase 82 U, the SGOT 47 U and the LDH 231 U. Therapy with cefazolin and gentamicin was begun after blood, sputum, urine and bone marrow specimens were taken for culture but were discontinued after three days when all cultures were negative. Spiking temperatures to 40’C continued nightly, and the white blood cell count fell to 1,600/mm3. The possibility of isoniazid- or rifampin-induced hepatitis was considered, and on the sixth hospital day the administration of isoniazid and rifampin was discontinued. A repeat bone marrow specimen showed granulomas consistent with tuberculosis. Numerous acid-fast bacilli were again seen on smear. Spiking fevers continued and on the 10th hospital day antituberculosis therapy, consisting of isoniazid 1300 mg/day), rifampin (600 mg/day) and ethambutol (15 mg/kg/day) was reinstituted. Skin tests with second strength purified protein derivative and tests for atypical mycobacteria yielded negative results. On the 35th hospital day the diagnosis of leprosy was first considered because of negative mycobacterial cultures in the face of unequivocal acid-fast disease and poor response to therapy. Acid-fast stains of the buffy coat of the patient’s blood did not reveal bacilli. Biopsy of skin from ear and elbow, examined by Fite stain, showed numerous acid-fast bacilli, compatible with the diagnosis of lepromatous leprosy. Therapy with dapsone (25 mg three times weekly] was initiated, ri-
Volume 67
fampin maintainc:d and other anti-tuberculous chemotherapy discontinuted. Over the next three weeks the liver function test results return4 to normal, and the patient became afebrile and improved clinically The white blood cell count rose slowly to the IO\Qnormal range and the platelet count to 200,ooWmm3. The patient was discharged on the 84th hospital day, after 42 days of dapsont: therapy, markedly improved. The dose of tlapsonc: was increased gradually to 50 mg/day, treatment with bvhich \vill continue for life. Except for stable, mild, stocking-glove hypocsthesia, the patient has been entirely well since tlischargc with normal liver function studies and return of liver ant1 spleen to normal size.
COMMENTS Like tuberculosis, lcpromatous leprosy is a systemic disease in which mycobacteria are widely disseminated throughout the body, surviving and multiplying in selective sites that are advantageous to its growth, such as skin, mucous membranes, peripheral nerves and testes. Organs with phagocytic function, particularly liver, spleen, bone marrow and lymph nodes, are often involved in association with the bacillemia, which is common in advanced disease and during acute exacerbations [G]. In our patient, hepatic granulomas were associated with liver function abnormalities. In a study of 240 leprosy patients in India, 62 per cent of the cases of lepromatous leprosy were associated with granulomatous lesions and altered liver function [7]. The presence of acid-fast bacilli in the liver correlated with the duration of disease and extent of leprous granulomas. Acid-fast bacilli were found to persist in liver long after clearance of acid-fast bacilli from the skin during therapy (71. Bone marrow involvement is also common and may occw independently of hepatic disease. In Karat’s study of 68 patients who had been receiving therapy for a year or more, 11 had acid-fast bacilli in both liver and bone marrow, nine in liver only and nine in marrow alone [7]. Bone marrow dysfunction in association with leprous in\rolvcment has not been described, but our patient’s panc!,topenia may have been related to extensive marrow infiltration. Pancytopenia in association with tubcrculous marrow involvement is known but is extremely uncommon. Although the classic cutaneous lesions of leprosy may 1~ recognizable even to the inexperienced observer, cutaneous involvement may be so subtle or inapparent that the diagnosis is overlooked until the disease has progressecl tn an advanced stage [8]. In Africa, this form of skin involvement is thought to account for about 10 per cent of all GISDS. In a report describing 13 such paticnts. Brown noted, however, that every patient had at least ono additional feature of advanced disease that had heen overlooked and that all patients had positive skin smears with high bacterial indices [9]. The faint, diffuse. macular eruption with which our patient presented ma!; have been an example of this type of confluent macular lcpromatous leprosy, and the history of
pruritic erythematous plaques may have represented an antecedent stage of the disease. Our patient’s course was characterized by two severe exacerbations of disease with hectic fevers, pancytopenis, derangement of liver function and marked clinical deterioration. The first episode was thought consistent with disseminated tuberculosis when acidfast bacilli were noted on bone marrow biopsy and after the patient seemed to respond to antituberculous chemotherapy with isoniazid and rifampin. The second episode, in which abnormal liver function tests were an especially prominent part of the clinical picture, \WS initially thought to represent hepatitis in a patient receiving two hepatotoxic antituberculous drugs. Retrospectively, both episodes were consistent with lepra reactions. These acute manifestations of leprosy may occur spontaneously or in response to therapy and may last from hours to weeks [lo-~]. They usually occur in patients with generalized and advanced lepromatous disease [F]. Although the mechanism of the lepra reaction is unknown, reactions following initiation of appropriatc chemotherapy may bc caused by the return of previously depressed cellular immunity and as such may be manifestations of a type of Arthus phenomenon [4,13-251. Our patient’s course is consistent with this hypothesis: since rifampin as an antileprosy clrug is as good or better than the traditional sulfones [ 16-191, our patient was inadvertently-and serendipitously-receiving appropriate antileprosy chemotherapy even before the correct diagnosis was apprcciatetl. Other patients with leprosy that we have treated ivith rifnmpin have had similar lepra reactions. Reasons for delays in recognition of leprosy are failure to examine the entire skin surface and perform bacteriologic examination of skin even when cutaneous involvement is uncertain. Blind skin biopsies may prove the diagnosis [g]. Powell ant1 McDougall [I] described eight patients in whom delays in diagnosis ranged from months to several years and pointed out that in each case consideration of the diagnosis bvould have: led to elicitation of cutaneous or ncurologic findings suggestive of leprosy that were present, but whose significance was unrecognized when the patients first came to mcclicnl attention. There are several important points to be iearned from our patient’s case. Leprosy should br: ctirnsiderecl in patients with multisystem illnesses who came from the appropriate epidemiologic setting. The liver and bone marrow, traditional extrapulmonary hunting grounds for pllrsuing the diagnosis of disscminatcd tuberculosis, are also favored sites for Mycobacterium leprae: therefore the demonstration of acid-fast bacilli in tither of these sites is not necessarily pathognomonic of tuberculosis. Indeed, it is extremely rare to find sheets of acid-fast bacilli in disseminated tuberculosis. Furthermore, growth of VI. tuberculosis from bono marrow samples is rapid: therefore, l’ailurc of growth with the newer media after three weeks should C~LISC one to
July 1979
The American
Journal of Medicine
Volume
67
115
DISSEMINATED LEPROMATOUS LEPROSY-WEISSMAN,
NEU
leprosy. Anergy, extremely common in lepromatous leprosy, also occurs in disseminated tuberculosis, but most patients with tuberculosis after several weeks of therapy and improved nutrition have positive skin tests. Hence, persistently negative skin tests should further heighten the suspicion of nontuberculous mycobacterial disease, as should the failure of biopsy material known to contain acid-fast bacilli to grow in culture. Skin smears and nasal scrapings, two high-yield procedures with negligible cost or morbidity, should be performed as diagnostic procedures of choice when
suspect
leprosy is considered in the differential diagnosis [1,20]. Demonstration of acid-fast bacilli in numbers in a marrow aspirate should prompt stains of the buffy coat of peripheral blood since a high bacillemia is present in severe lepromatous leprosy. Lastly, it is worth noting that in every reported case in which diagnosis was delayed [including this one), physical findings indicative of leprosy were present but were overlooked, underscoring yet again that the importance of a careful clinical examination cannot be overemphasized and that a diagnosis which is not considered will not be made.
REFERENCES 1. Powell S, McDougall C: Clinical recognition of leprosy. Some factors leading to delays in diagnosis. Br Med J 1: 612,
Leprosy 33: 570,1965. 11. Yawakjar SJ: Reactions in leprosy. Leprosy for Practitioners,
Bombay, Popular Prakashan, 1967, p 48.
1974.
2.
Lele RD, Sainani GS, Sharma KD: Leprosy presenting as rheumatoid arthritis. 1 Assoc Phvsicians India 13: 275,
1965. 3. Modi TH, Lele RD: Acute joint manifestations in leprosy. J Assoc Physicians India 17:247,1969. 4. Iveson JMI, McDougall AC, Leathem AJ, et al.: Lepromatous
leprosy presenting with polyarthritis, myositis. and immune complex glomerulonephritis. Br Med J 3: 619,1975. 5. Sinkovics JG. Ibanez ML: The elusive diagnosis of leprosy. Postgraduate Med 55: 199.1970. 6. Muir E. Manual of Leprosy. Baltimore, Williams & Wilkins, 1948, p 31. 7. Karat ABA, et al.: Acute exudative arthritis in leprosyrheumatoid-arthritis-like syndrome in association with erythema nodosum leprosum. Br Med J 3:770.1967. 8. Davey TF: Masked lepromatous leprosy. Leprosy Rev 13:3, 1942. 9. Browne SG: Confluent macular lepromatous leprosy. Leprosy
Rev 36: 157,1965. 10. Tolentino JG: Acute manifestations
116
July 1979 The American
12. Donner RS, Shively JA. The “Lucia Phenomenon” 13.
14. 15.
16. 17.
18. 19. 20.
of leprosy. Internat J
Journal of Medicine
Volume
67
in diffuse leurosv. Ann Intern Med 67: 831.1967. Bullbck WE: Studies of immune mechanisms in leprosy. I. Depression of delayed allergic response to skin test antigens. N Engl J Med 278: 298,1968. Cochrane RG, Davey TF: Leprosy in Theory and Practice. Bristol, John Wright & Sons, Ltd., 1964, pp 152.346 Wemambu SNC, Turk JL, Waters MFR. et al.: Erythema nodosum leprosum. A clinical manifestation of the arthus uhenomenon. Lancet 2: 933,1969. Editorial. Antileprosy drugs. Br Med J 3: 174.1971. Rees RIW. Pearson IMH. Waters MFR: Exuerimental and clinical studies on’rifampicin in treatment of leprosy. Br Med J 1:89,1970. Rees RJW: Rifampicin. The investigation of a bactericidal antileprosy drug. Leprosy Rev 46 (suppl]: 121,1975. Browne SC: The drug treatment of leprosy. Practitioner 215: 493,1975. Khandlar VR: Diagnosis of leprosy. Leprosy Rev 32: 158, 1961.
Lepromatous Leprosy Masquerading As Disseminated Tuberculosis
IA(:K
B. WEISSMAN,
HAROLD
M.D.
C. NEU. M.D.
NI:IVYork, New York
A patient with disseminated leprosy is described. A 57 year old man from Cuba presented with fever and pancytopenia. Bone marrow aspirate showed numerous acid-fast bacilli and a liver biopsy specimen contained multiple granulomas. The patient was considered to have tuberculosis and was treated with isoniazid and rifampin, with initial clinical improvement, only to have the fever recur and to show deterioration in hematologic and hepatic function. Failure to grow M. tuberculosis suggested a diagnosis of leprosy which was proved by skin biopsy. How lepromatous leprosy can masquerade as disseminated tuberculosis is discussed. The protean manifestations, chronic course and infrequent occurrence of leprosy in the [Jnited States contribute to difficulties in early rccognition and diagnosis of this disease. Since leprosy is endemic in man! Caribbean countries, it is likely that urban centers with large immigrant communities harbor many patients with the disease. Leprosy may bc unrecognized either because it is not considered in the differential diagnosis or because it “masquerades” as another disease. The cutaneous manifestations of leprosy have been confused with systemic lupus erythematosus, psoriasis, erythema multiforme and cutaneous allergies [I]; the ncurologic manifestations have been confused with syringomyelia; the systemic manifestations with rheumatoid arthritis [2,3], polyarteritis nodosa [1,4], glomerulonephritis [4] and septicemia [1,4.5]. In most situations, definitive diagnosis becomes apparent when ;I biopsy specimen of appropriate material discloses acid-fast bacilli and the typical pathology. We describe here a patient in whom the diagnosis of leprosy was delayed, despite coml)atible biopsy material, 1~ca1~ of the similarity to disseminated tuberculosis. CASE REPORT A 57 year old construction Mcclical years
From the Department of Medicine, Division of Infectious Diseases. College of Physicians and Surgeons, Columbia Ilniversity and Medical Service, Presbyterian Hospital. New York, New York. Requests for reprints should bc addressed to Dr. Harold C. Neu. 630 West 168 Street, New York. New York 10032. Manuscript accepted N(,vcmbcr 8, 11f78.
Center
earlier
because
to the United
worker
was admitted
of fever States
and shaking from Cuba.
to the Columl)i;l-~‘rcsl,~t~~ri~lrl chills.
Hc hatI c,migr;ltctl
Hc had txxn
tight
well until twoyc;trs
prior to admission when erythcm;ltous. pruritic plaq~~cs clcvcl~~~~ctl (III his trunk and arms that rcsolvcd after scvcrol weeks of topical thcr;lpy. ‘I’cn ;lays IIcforc admission he noted malaise and Icthargy which, five days I;ltc:r. wcrc follo~~t:d by fever with temperatures to 4VC. shaking chills and antrrcuia. Hc had no cough, hemoptysis, chest pain, weight loss or headache. On admission the patient’s tcmpcraturc was 40”C, the bloocl lxcssrlrc SO/GO mm Hg, the pulse rate 130/min and thready. A faint c:rythorn,~tcnls mac111a1. crrlption was present. His livc:r was enlarged to 1-t cm in spn. but the: spleen was not palpable and thcrc w:fs no Iyml,h~ldanoi,ath\‘.
July 1979
The American
Journal
of Medicine
Volume
67
113
DISSEMINATED
LEPROMATOUS
LEPROSY-WEISSMAN,
NEU
Figure 1. Multiple granulomas as illustrated between the arrows with caseating necrosis and Langhans’ giant cells.
The white blood cell count was 3,500/mm3 with 77 per cent neutrophils of which 13 were band forms. The hematocrit value was 33 per cent. The erythrocyte sedimentation rate was 90 mm/hour (Westergren). The urea nitrogen was 8 mg/dl; the serum electrolytes and clotting profile were within the normal range of values. His total protein was 5.2 g/d1 of which 2.5 g/d1 was albumin. The alkaline phosphatase was 69 U. the serum glutamic oxaloacetic transaminase (SGOT) 39 LJ, the lactic dehydrogenase (LDH) 183 U and the bilirubin 0.5 mg/dl. A lumbar puncture was within normal limits. An x-ray film of the chest showed diffuse, mild peripheral interstitial scarring suggestive of chronic interstitial pulmonary disease. A specimen of arterial blood, drawn with the patient breathing room air, showed a pH of 7.51, a oxygen tension (~0~) of 87 mm Hg, and a carbon dioxide tension (pC0~) of 31 mm Hg. Multiple blood cultures were negative, as were cultures of urine and cerebrospinal fluid. Therapy with ampicillin and gentamicin was initiated since sepsis was suspected. The white blood cell count fell to 2,300/mm3 and the hematocrit value fell to 26 per cent with normochromic, normocytic indices. The platelet count declined to 9O,OOO/mms. Although the patient’s fever persisted, when cultures were negative antibiotics therapy was discontinued. The bilirubin level rose to 2.8 mg/dl, the SGOT to 70 U and the alkaline phosphatase to 146 U. A bone marrow aspirate on the fifth hospital day showed numerous acid-fast bacilli, and a diagnosis of disseminated tuberculosis was made. Therapy with isoniazid (300 mg daily] and rifampin (600 mg daily) was initiated. Fever, leukopenia and abnormal liver function tests persisted: a percutaneous liver biopsy specimen obtained after one week of antituberculous chemotherapy showed multiple granulomas (Figure 1). The patient became afebrile over the following week and remained afebrile after 14 days of therapy
114
July 1979
The American Journal of Medicine
with isoniazid and rifampin. His SGOT and LDH values became normal by the 21st hospital day. The patient was readmitted two weeks after discharge because of recurrence of fever, nausea and anorexia. The liver was now 11 cm in span and the spleen was palpable 3 cm below the costal margin. The hematocrit value was 26 per cent, the white blood cell count 4,000/mm3 and the sedimentation rate 150 mm/hour. A chest film again showed diffuse interstitial infiltrates. The bilirubin was 1.5 mg/dl, the alkaline phosphatase 82 U, the SGOT 47 U and the LDH 231 U. Therapy with cefazolin and gentamicin was begun after blood, sputum, urine and bone marrow specimens were taken for culture but were discontinued after three days when all cultures were negative. Spiking temperatures to 40’C continued nightly, and the white blood cell count fell to 1,600/mm3. The possibility of isoniazid- or rifampin-induced hepatitis was considered, and on the sixth hospital day the administration of isoniazid and rifampin was discontinued. A repeat bone marrow specimen showed granulomas consistent with tuberculosis. Numerous acid-fast bacilli were again seen on smear. Spiking fevers continued and on the 10th hospital day antituberculosis therapy, consisting of isoniazid 1300 mg/day), rifampin (600 mg/day) and ethambutol (15 mg/kg/day) was reinstituted. Skin tests with second strength purified protein derivative and tests for atypical mycobacteria yielded negative results. On the 35th hospital day the diagnosis of leprosy was first considered because of negative mycobacterial cultures in the face of unequivocal acid-fast disease and poor response to therapy. Acid-fast stains of the buffy coat of the patient’s blood did not reveal bacilli. Biopsy of skin from ear and elbow, examined by Fite stain, showed numerous acid-fast bacilli, compatible with the diagnosis of lepromatous leprosy. Therapy with dapsone (25 mg three times weekly] was initiated, ri-
Volume 67
fampin maintainc:d and other anti-tuberculous chemotherapy discontinuted. Over the next three weeks the liver function test results return4 to normal, and the patient became afebrile and improved clinically The white blood cell count rose slowly to the IO\Qnormal range and the platelet count to 200,ooWmm3. The patient was discharged on the 84th hospital day, after 42 days of dapsont: therapy, markedly improved. The dose of tlapsonc: was increased gradually to 50 mg/day, treatment with bvhich \vill continue for life. Except for stable, mild, stocking-glove hypocsthesia, the patient has been entirely well since tlischargc with normal liver function studies and return of liver ant1 spleen to normal size.
COMMENTS Like tuberculosis, lcpromatous leprosy is a systemic disease in which mycobacteria are widely disseminated throughout the body, surviving and multiplying in selective sites that are advantageous to its growth, such as skin, mucous membranes, peripheral nerves and testes. Organs with phagocytic function, particularly liver, spleen, bone marrow and lymph nodes, are often involved in association with the bacillemia, which is common in advanced disease and during acute exacerbations [G]. In our patient, hepatic granulomas were associated with liver function abnormalities. In a study of 240 leprosy patients in India, 62 per cent of the cases of lepromatous leprosy were associated with granulomatous lesions and altered liver function [7]. The presence of acid-fast bacilli in the liver correlated with the duration of disease and extent of leprous granulomas. Acid-fast bacilli were found to persist in liver long after clearance of acid-fast bacilli from the skin during therapy (71. Bone marrow involvement is also common and may occw independently of hepatic disease. In Karat’s study of 68 patients who had been receiving therapy for a year or more, 11 had acid-fast bacilli in both liver and bone marrow, nine in liver only and nine in marrow alone [7]. Bone marrow dysfunction in association with leprous in\rolvcment has not been described, but our patient’s panc!,topenia may have been related to extensive marrow infiltration. Pancytopenia in association with tubcrculous marrow involvement is known but is extremely uncommon. Although the classic cutaneous lesions of leprosy may 1~ recognizable even to the inexperienced observer, cutaneous involvement may be so subtle or inapparent that the diagnosis is overlooked until the disease has progressecl tn an advanced stage [8]. In Africa, this form of skin involvement is thought to account for about 10 per cent of all GISDS. In a report describing 13 such paticnts. Brown noted, however, that every patient had at least ono additional feature of advanced disease that had heen overlooked and that all patients had positive skin smears with high bacterial indices [9]. The faint, diffuse. macular eruption with which our patient presented ma!; have been an example of this type of confluent macular lcpromatous leprosy, and the history of
pruritic erythematous plaques may have represented an antecedent stage of the disease. Our patient’s course was characterized by two severe exacerbations of disease with hectic fevers, pancytopenis, derangement of liver function and marked clinical deterioration. The first episode was thought consistent with disseminated tuberculosis when acidfast bacilli were noted on bone marrow biopsy and after the patient seemed to respond to antituberculous chemotherapy with isoniazid and rifampin. The second episode, in which abnormal liver function tests were an especially prominent part of the clinical picture, \WS initially thought to represent hepatitis in a patient receiving two hepatotoxic antituberculous drugs. Retrospectively, both episodes were consistent with lepra reactions. These acute manifestations of leprosy may occur spontaneously or in response to therapy and may last from hours to weeks [lo-~]. They usually occur in patients with generalized and advanced lepromatous disease [F]. Although the mechanism of the lepra reaction is unknown, reactions following initiation of appropriatc chemotherapy may bc caused by the return of previously depressed cellular immunity and as such may be manifestations of a type of Arthus phenomenon [4,13-251. Our patient’s course is consistent with this hypothesis: since rifampin as an antileprosy clrug is as good or better than the traditional sulfones [ 16-191, our patient was inadvertently-and serendipitously-receiving appropriate antileprosy chemotherapy even before the correct diagnosis was apprcciatetl. Other patients with leprosy that we have treated ivith rifnmpin have had similar lepra reactions. Reasons for delays in recognition of leprosy are failure to examine the entire skin surface and perform bacteriologic examination of skin even when cutaneous involvement is uncertain. Blind skin biopsies may prove the diagnosis [g]. Powell ant1 McDougall [I] described eight patients in whom delays in diagnosis ranged from months to several years and pointed out that in each case consideration of the diagnosis bvould have: led to elicitation of cutaneous or ncurologic findings suggestive of leprosy that were present, but whose significance was unrecognized when the patients first came to mcclicnl attention. There are several important points to be iearned from our patient’s case. Leprosy should br: ctirnsiderecl in patients with multisystem illnesses who came from the appropriate epidemiologic setting. The liver and bone marrow, traditional extrapulmonary hunting grounds for pllrsuing the diagnosis of disscminatcd tuberculosis, are also favored sites for Mycobacterium leprae: therefore the demonstration of acid-fast bacilli in tither of these sites is not necessarily pathognomonic of tuberculosis. Indeed, it is extremely rare to find sheets of acid-fast bacilli in disseminated tuberculosis. Furthermore, growth of VI. tuberculosis from bono marrow samples is rapid: therefore, l’ailurc of growth with the newer media after three weeks should C~LISC one to
July 1979
The American
Journal of Medicine
Volume
67
115
DISSEMINATED LEPROMATOUS LEPROSY-WEISSMAN,
NEU
leprosy. Anergy, extremely common in lepromatous leprosy, also occurs in disseminated tuberculosis, but most patients with tuberculosis after several weeks of therapy and improved nutrition have positive skin tests. Hence, persistently negative skin tests should further heighten the suspicion of nontuberculous mycobacterial disease, as should the failure of biopsy material known to contain acid-fast bacilli to grow in culture. Skin smears and nasal scrapings, two high-yield procedures with negligible cost or morbidity, should be performed as diagnostic procedures of choice when
suspect
leprosy is considered in the differential diagnosis [1,20]. Demonstration of acid-fast bacilli in numbers in a marrow aspirate should prompt stains of the buffy coat of peripheral blood since a high bacillemia is present in severe lepromatous leprosy. Lastly, it is worth noting that in every reported case in which diagnosis was delayed [including this one), physical findings indicative of leprosy were present but were overlooked, underscoring yet again that the importance of a careful clinical examination cannot be overemphasized and that a diagnosis which is not considered will not be made.
REFERENCES 1. Powell S, McDougall C: Clinical recognition of leprosy. Some factors leading to delays in diagnosis. Br Med J 1: 612,
Leprosy 33: 570,1965. 11. Yawakjar SJ: Reactions in leprosy. Leprosy for Practitioners,
Bombay, Popular Prakashan, 1967, p 48.
1974.
2.
Lele RD, Sainani GS, Sharma KD: Leprosy presenting as rheumatoid arthritis. 1 Assoc Phvsicians India 13: 275,
1965. 3. Modi TH, Lele RD: Acute joint manifestations in leprosy. J Assoc Physicians India 17:247,1969. 4. Iveson JMI, McDougall AC, Leathem AJ, et al.: Lepromatous
leprosy presenting with polyarthritis, myositis. and immune complex glomerulonephritis. Br Med J 3: 619,1975. 5. Sinkovics JG. Ibanez ML: The elusive diagnosis of leprosy. Postgraduate Med 55: 199.1970. 6. Muir E. Manual of Leprosy. Baltimore, Williams & Wilkins, 1948, p 31. 7. Karat ABA, et al.: Acute exudative arthritis in leprosyrheumatoid-arthritis-like syndrome in association with erythema nodosum leprosum. Br Med J 3:770.1967. 8. Davey TF: Masked lepromatous leprosy. Leprosy Rev 13:3, 1942. 9. Browne SG: Confluent macular lepromatous leprosy. Leprosy
Rev 36: 157,1965. 10. Tolentino JG: Acute manifestations
116
July 1979 The American
12. Donner RS, Shively JA. The “Lucia Phenomenon” 13.
14. 15.
16. 17.
18. 19. 20.
of leprosy. Internat J
Journal of Medicine
Volume
67
in diffuse leurosv. Ann Intern Med 67: 831.1967. Bullbck WE: Studies of immune mechanisms in leprosy. I. Depression of delayed allergic response to skin test antigens. N Engl J Med 278: 298,1968. Cochrane RG, Davey TF: Leprosy in Theory and Practice. Bristol, John Wright & Sons, Ltd., 1964, pp 152.346 Wemambu SNC, Turk JL, Waters MFR. et al.: Erythema nodosum leprosum. A clinical manifestation of the arthus uhenomenon. Lancet 2: 933,1969. Editorial. Antileprosy drugs. Br Med J 3: 174.1971. Rees RIW. Pearson IMH. Waters MFR: Exuerimental and clinical studies on’rifampicin in treatment of leprosy. Br Med J 1:89,1970. Rees RJW: Rifampicin. The investigation of a bactericidal antileprosy drug. Leprosy Rev 46 (suppl]: 121,1975. Browne SC: The drug treatment of leprosy. Practitioner 215: 493,1975. Khandlar VR: Diagnosis of leprosy. Leprosy Rev 32: 158, 1961.
