You are on page 1of 8

1139

Disseminated Bacille Calmette-Guerin Disease After Vaccination: Case Report and Review
Elizabeth A. Talbot, Mark D. Perkins, Sandra Fagundes M. Silva, and Richard Frothingham
From the Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, and the Infectious Diseases Section, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA; and the Infectious Diseases Unit, Federal University of Espirito Santo, Vitoria, Brazil

The attenuated bacille Calmette-Guerin (BCG) vaccine is administered to prevent tuberculosis. Complications of vaccination are uncommon. We report a new case of disseminated BCG disease and review 27 additional cases identied from a review of 5,000 reports published between 1980 and 1996. Twenty-four of the 28 total cases were associated with an immune deciency, including nine cases of AIDS. Seventy-one percent of the cases occurred in children younger than 2 years old. Sixty-eight percent of the patients were male. About one-half of the patients were vaccinated in a developed nation, but 85% of the cases were reported from a developed nation. Response to therapy was poor, with an overall mortality rate of 71%. We made two new observations. Disseminated BCG disease has historically been a disease of infants, but cases now occur in adults and older children coinfected with human immunodeciency virus. Cases also occur after revaccination of individuals who were anergic following the initial administration of BCG vaccine. Disseminated BCG disease is an uncommon but devastating complication of vaccination that should be considered in the appropriate clinical setting. Immunocompromised infants and patients with late-stage AIDS are at greatest risk and respond poorly to standard therapies.

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

The original BCG strain of Mycobacterium bovis was derived from multiple passages of wild-type M. bovis [1]. BCG vaccine is administered worldwide to prevent tuberculosis and is considered to have an excellent safety prole. However, complications do occur, including abscesses at the site of inoculation and localized lesions such as osteitis [2]. The most serious complication is disseminated disease. We report a new case of disseminated BCG disease in an infant with immunodeciency. We also present a working denition of disseminated BCG disease, which we use to review the literature on disseminated BCG disease resulting from vaccination. We identied 28 denite [3 21] and nine probable [22 28] cases reported from 1980 through 1995, a period that overlaps minimally with those of a previous retrospective review [29] and a prior prospective study [30]. The topic of disseminated BCG disease warrants reevaluation, given improved diagnostic methods, an expanded concept of disseminated mycobacterial disease, and the progression of the AIDS epidemic. Case Report An 8-month-old girl presented to a pediatric hospital in Vitoria, Brazil, with a 3-week history of bloody diarrhea, cough,

Received 10 April 1996; revised 26 November 1996. Financial support: This work was supported by the National Institutes of Health (AI07392 and AI35230) and the Department of Veterans Affairs. Reprints or correspondence: Dr. Richard Frothingham, Veterans Affairs Medical Center, 508 Fulton Street, Building 4, Durham, North Carolina 27705.
Clinical Infectious Diseases 1997;24:113946 1997 by The University of Chicago. All rights reserved. 10584838/97/24060017$02.00

and fever; her family history was unavailable. Her medical history revealed that she had had frequent illnesses since birth, including bronchiolitis, pneumonia, and chronic bloody diarrhea. Immunization over the right deltoid muscle with Moreau BCG vaccine (Fundao Ataufo de Paiva, Rio de Janeiro) at 10 days of age had resulted in a nonhealing ulcer. One month before admission, the child developed dyspnea, productive cough, abdominal distention, increased diarrhea, fever, and an enlarging right axillary mass. At the time of admission, the child had a temperature of 38.9 C and labored breathing. She appeared pale and listless and had moderate thrush. The site of BCG vaccination was enlarged, erythematous, and weeping. A soft, mobile right axillary lymph node (5 cm in size) was present. There were diffuse rhonchi. Abdominal examination showed distention, hepatosplenomegaly, and a rm, mobile 3-cm mass in the epigastrium. Laboratory studies at the time of admission revealed a WBC count of 12,700/mm3 (10% lymphocytes), hematocrit of 17%, and platelet count of 118,000/mm3. Testing for antibody to HIV by ELISA was negative twice. Ultrasonography conrmed the presence of a heterogeneous abdominal mass measuring 3.0 1 6.2 cm. A tuberculin test was nonreactive, and microscopic examinations of sputum and gastric aspirates were negative for acidfast bacilli. However, biopsies of the axillary and abdominal masses yielded lymph tissue that was 3/ positive for acid-fast organisms. A presumptive diagnosis of disseminated tuberculosis was made, and therapy with isoniazid, rifampin, and pyrazinamide was begun. The infant remained febrile, developed progressive leukopenia and hypoxemia, and died on the 29th day of therapy. Necropsy showed pulmonary Pneumocystis

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID

1140

Talbot et al.

CID 1997;24 (June)

carinii infection, esophageal candidiasis, and diffuse lymphadenopathy. Well-developed granulomas and many acid-fast bacilli were found in both the liver and spleen.

according to the working denition shown in table 2. The rationale for this denition is presented under Discussion. Results

Methods Culture and identication. The biopsy sample from the abdominal mass was cultured, and the isolate was identied to the species level by growth inhibition by p-nitroacetylaminohydroxypropiophenone and thiophene-2-carboxylic acid hydrazide, nitrate reduction, and niacin production. Drug susceptibility testing was performed by means of the BACTEC System (Becton Dickinson, Sparks, MD). Two additional methods were used to conrm the identity of the isolate as BCG. A specic genomic region containing the major polymorphic tandem repeat (MPTR) was amplied by PCR analysis, and restriction enzyme analysis (REA) was carried out according to the published method [31]. HPLC was performed by the Centers for Disease Control and Prevention as previously described [32]. Literature search and case classication. We conducted a literature search by using MEDLINE with the subject heading terms Mycobacterium bovis BCG, BCG vaccine, and bacillus Calmette-Guerin and the text words BCG, Calmette, and Guerin. We limited our search to the English- and French language literature from 1980 through 1995. We also conducted a literature search by using the Latin American and Caribbean Health Sciences Literature of the Pan-American Health Organization Library with use of a similar search strategy. These databases include literature published since 1985. Reference lists of case reports, trials, and reviews were also examined for relevant articles. Cases resulting from any mechanism other than vaccination (e.g., intravesical instillation of BCG for the treatment of bladder cancer) were excluded from analysis. Cases identied by the literature searches were classied according to table 1. Each potential case of disseminated disease was then evaluated

Table 1. Classication of complications following BCG vaccination.


Category
Regional disease

Description
Persistent ulcer, abscess, stula, or lymphadenopathy limited to the region of inoculation. Infection of a single anatomic site, such as osteitis or cutaneous abscess, outside the region of inoculation. See detailed denition in table 2. Syndromes following vaccination in which bacteria are not identied, such as keloid formation and uveitis. These syndromes may have an immune basis.

Extraregional localized disease Disseminated disease Other BCG syndromes

NOTE. Data are adapted from [30].

Case. The isolate from the abdominal mass in our patient was identied as BCG by the methods described above [31 33]. The isolate was susceptible to isoniazid, rifampin, streptomycin, and ethambutol and was resistant to pyrazinamide. Our case was classied as denite disseminated disease on the basis of evidence of infection at three extraregional sites (abdominal lymph node, liver, and spleen) and a systemic syndrome consistent with mycobacterial disease (fever, weight loss, anemia, and death). Literature review and case classication. We reviewed 5,000 reports and identied 27 additional cases of denite disseminated BCG disease that were reported from 1980 through 1995; these cases are summarized in table 3. Seventyone percent (20) of 28 cases occurred in patients younger than 2 years of age. Four cases occurred in adults. Sixty-eight percent of patients for whom sex was reported were male. Eightysix percent (24) of 28 cases occurred in immunocompromised hosts. AIDS was identied in 32% of all cases. Other immunodeciencies included severe combined immunodeciency (ve patients), chronic granulomatous disease (three), and unidentied cell-mediated immune defects (seven). Sites of dissemination were established by culture or histological demonstration of acid-fast bacilli. The most common sites of dissemination were lymph nodes, which were identied in 24 of 28 cases. Blood or bone marrow was positive for BCG in nine cases. Other common sites of dissemination were the lung, liver, spleen, skin, and bone. The most commonly reported symptoms in the denite cases of disseminated BCG disease were fever, lymphadenopathy, and weight loss. Failure to thrive and hepatosplenomegaly were also common. Reporting of symptoms was incomplete, and associating symptoms with disseminated BCG disease was sometimes difcult because of comorbid illnesses. Most therapeutic regimens included at least isoniazid and rifampin. The mortality rate was 78% among patients with AIDS, 83% among all immunocompromised patients, and 0 among patients without an identied immunodeciency. Mortality attributable to BCG disease was difcult to determine, given the frequency of other opportunistic infections. In nine additional cases, there was not enough information to satisfy the working denition of denite disseminated BCG disease. These cases are summarized in table 4. Many of these cases probably represented disseminated BCG disease on the basis of other features; clinicians appropriately treated these patients and reported data on the basis of available information. These probable cases were not included in the above analyses, but there were many similarities between the denite and probable cases. Most patients were immunocompromised male infants from developing nations who presented with fever. The organism

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID

CID 1997;24 (June)

Disseminated BCG Disease

1141

Table 2. Working denition of disseminated BCG disease.


Cases were dened as denite disseminated BCG disease when all three of the following conditions were met. 1. BCG cultured and identied by biochemical methods at least. 2. Dissemination evidenced by either A or B. A. A positive blood or bone marrow culture. B. Evidence of infection at two or more anatomic sites beyond the region of vaccination. Evidence of infection includes a positive culture or histopathologic demonstration of acid-fast bacilli. Examples of acceptable sites include the following: lymph node or nodes beyond the ipsilateral axillary lymph nodes; one or more cutaneous abscesses beyond the region of vaccination; osteomyelitis at one or more sites; brain or CSF; lung biopsy specimen, sputum, pleura and/or pleural uid, or gastric aspirate; liver; spleen; intestine and/or stool; and kidney and/or urine. Multiple isolates from the same organ system are counted only once. For example, infection of multiple distant lymph nodes constitutes one site. Isolation of BCG from both sputum and pleural uid constitutes one site. 3. A systemic syndrome compatible with mycobacterial disease. Typical manifestations include fever, weight loss, anemia, and death.

was often identied in the lymph nodes, and the mortality rate was high despite aggressive antimicrobial therapy.

Discussion Background. The original BCG strain was derived from M. bovis and was rst used as a tuberculosis vaccine in 1921. Over 3 billion doses of BCG vaccine have been given since 1948, and it has been considered to be safe [1]. However, complications do occur. Lotte et al. [29] reviewed 1,000 reports and found that 10,000 complications of BCG vaccination were reported between 1921 and 1982. Their retrospective review identied 60 cases of dissemination for which the mortality rate was 50%. In a later prospective survey of complications of BCG vaccination [30], the same researchers studied all infants vaccinated between 1979 and 1981 in six European countries. The 5.5 million infants who were vaccinated were followed up through 1983 by means of a questionnaire. The estimated incidence of disseminated disease was 2 cases per 1 million vaccinated children, and the mortality rate was 80%. BCG disease and immunodeciencies. Serious complications of BCG vaccination, such as generalized lymphadenitis [34] and disseminated disease [35], do occur in normal hosts, but these complications are exceptional. In the retrospective review of disseminated BCG disease by Lotte et al. [29], cellular immunodeciency was identied as the chief risk factor for fatal outcome. Of the 60 total patients who were identied, 31 died. All patients who died had a denite or highly probable cellular immunodeciency. Twenty-nine patients recovered. Eleven of these 29 patients also had a partial or serious immune defect. Our literature review conrms a predilection of disseminated BCG disease in immunocompromised hosts. Immune defects

were identied in 24 of the 28 denite cases. Of the 20 patients who died of disseminated BCG disease, all had an immune defect. In contrast, of the eight patients who recovered, only four had an identied immunodeciency. BCG disease and HIV infection. There have been many reports of local complications of BCG vaccination in patients with HIV infection, especially abscesses, adenitis, and stulae. These local complications of BCG vaccination have occurred in patients with both symptomatic and asymptomatic HIV infection [36 41]. Symptomatic HIV-infected patients who are immunized with BCG vaccine have developed the devastating complication of disseminated disease (cases 9 and 30). Whether asymptomatic HIV-infected patients who are immunized with BCG vaccine are at increased risk for disseminated disease is more controversial. There have been reports suggesting that this is true [42]; cases 1, 6, 7, and 31 also suggest that asymptomatic HIVinfected patients who are immunized with BCG vaccine are at increased risk. There has even been one case of apparent reactivation of BCG disease and symptomatic dissemination that occurred in a patient with AIDS 30 years after vaccination (case 4); this case suggests that HIV-infected patients can develop complications of BCG vaccination even if they are immunized with BCG vaccine before the acquisition of HIV infection. Not all cases of disseminated BCG disease in HIV-infected patients are reported. BCG vaccination is currently used where HIV infection is epidemic but testing for HIV infection is not routinely done. In the developing nations, lack of resources makes the routine and accurate identication of pathogens in patients with AIDS difcult. Disseminated BCG disease may be misdiagnosed as infection due to Mycobacterium tuberculosis or M. bovis. The relative paucity of cases in the developing world that were identied by our review and that of Lotte et al. [29] may reect incomplete reporting or reporting in sources not accessed by our search strategies. There have been prospective studies identifying the risk of disseminated disease in asymptomatic HIV-infected patients [4, 43 47]. One recent study [48] enrolled 155 adults with AIDS who had received BCG vaccination as children. Blood specimens for mycobacterial cultures were obtained at study entry and at 6 months. None of the cultures of specimens from these patients were positive for BCG. Most studies are small with inadequate follow-up; therefore, the actual risk to asymptomatic HIV-infected patients remains poorly characterized. Identication of BCG. Mycobacterial isolates are frequently identied in clinical microbiology laboratories to the level of the M. tuberculosis complex, which includes M. tuberculosis, M. bovis, Mycobacterium africanum, and Mycobacterium microti. Suspicion that an M. tuberculosis complex isolate may be BCG is often based on the clinical history (especially the temporal relationship between vaccination and disease) or the presence of disease in the region of vaccination. The combi-

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID

1142

Talbot et al.

CID 1997;24 (June)

Table 3. Summary of data on 28 denite cases of disseminated BCG disease that were reported from 1980 through 1995.
Case no. [reference]
1 [3] 2 [4] 3 [4] 4 [5] 5 [6] 6 [7] 7 [8] 8 [9] 9 10 11 12 13 [10] [11] [11] [11] [12]

Country: patient/report
Brazil/USA France/France France/France NR/Austria Argentina/Switzerland Canada (Native American)/ Canada Zaire/Belgium Haiti/French Guiana Mexico/USA Sweden/Sweden Sweden/Sweden Sweden/Sweden Chile/USA Chile/USA Chile/Chile Chile/Chile NR/Hungary Brazil/USA Chile/USA Chile/USA Chile/Chile Sweden/Sweden France/France Scotland/Scotland Algeria/France Sweden/Sweden Mexico/USA France/France

Age/sex
3 y/M 5 mo/NR 3 y/NR 31 y/M 8 mo/F 2.5 mo/F 4 mo/M 34 y/M 29 y/M 4 mo/F 5 mo/M 4 mo/M 6 mo/M 21 mo/NR 5 mo/M 18 mo/F 8 mo/M 8 mo/F 5 y/M 1.5 y/M 11 mo/F 4 mo/F 12 mo/M 18 y/M 1.5 mo/M 17 mo/M 3 y/F 1 y/M

Immune defect (CD4 cells/mm3)


AIDS AIDS (269) AIDS (120) AIDS AIDS AIDS (70) AIDS AIDS AIDS SCID SCID SCID SCID SCID CGD CGD CGD CMI CMI CMI CMI CMI CMI CMI None None None None

Conrmed site(s) of dissemination


Blood D LN, lung, liver D LN, spleen, peritoneum D LN, blood, urine, stool Liver, spleen, bone marrow Blood, gastric aspirate, lung LN, CSF LN, sputum, lung, kidney, urine, spleen R LN, blood LN, skin, urine LN, skin, bone LN, skin, CSF, bone marrow D and R LNs, skin, liver, spleen, lung, bones R LN, liver, spleen, lung, bones D LN, lung LN, lung LN, lung, intestine R LN, abdominal LN, liver, spleen D and R LNs, gastric aspirate D and R LNs, lung, bone Blood, urine R LN, bone marrow D LN, gastric aspirate, lung, skin, liver, spleen D LN, lung, liver, bone, peritoneum D LN, liver, spleen, lungs D LN, gastric aspirate, liver, bone marrow D LN, CSF, bone, bone marrow LN, skin, lung, gastric aspirates

Systemic syndrome
LAD, HM, SOB Fever, LAD, HSM Fever, sepsis Fever, weight loss Fever, LAD Fever, failure to thrive, HM, SOB Fever, failure to thrive, HSM, diarrhea Fever, LAD, weight loss, diarrhea Fever, fatigue Fever, failure to thrive Fever Fever Weight loss, LAD Weight loss, LAD Failure to thrive, LAD Failure to thrive, LAD LAD, HSM Fever, weight loss, anemia LAD LAD LAD, sepsis Fever, failure to thrive, LAD Fever, HSM Fever, weight loss, malaise, LAD, HSM Failure to thrive, LAD, HSM Fever, LAD, HSM Fever, failure to thrive Fever, LAD, weight loss, HSM

Antimicrobial therapy
NR INH, Rif, Eth, Clof NR INH, Rif, Eth, Stm NR INH, Rif INH, Rif, Eth INH, Rif, Eth INH, Eth NR NR NR NR NR Rif, Stm INH, Rif INH, Rif, Stm INH, Rif, PZA INH, Rif, Stm, Ethi, Eth INH, Rif, Stm, Eth INH, Rif, Stm INH, Rif, Stm, PZA INH, Rif, Ethi, Eth INH, Rif, Eth, Stm INH, Rif, Eth INH, Rif, Stm INH, Rif, Eth, PAS, Cyse INH, Rif, Eth, Stm

Outcome
Died Died Died Survived Died Died Died Died Survived Died Survived Died Died Died Died Died Died Died Died Died Died Survived Died Died Survived Survived Survived Survived

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

14 [12] 15 16 17 18 [13] [13] [14] [PR]

19 [12] 20 [12] 21 [13] 22 [15] 23 [16] 24 [17] 25 [18] 26 [19] 27 [20] 28 [21]

NOTE. CGD chronic granulomatous disease; Clof clofazimine; CMI cell-mediated immune defect; Cyse cycloserine; D distant; Eth ethambutol; Ethi ethionamide; HM hepatomegaly; HSM hepatosplenomegaly; INH isoniazid; LAD lymphadenopathy; LN lymph node; NR not reported; PAS p-aminosalicylic acid; PR present report; PZA pyrazinamide; R regional; Rif rifampin; SCID severe combined immunodeciency; SOB shortness of breath; Stm streptomycin.

nation of biochemical and growth features can strongly suggest that an isolate is BCG, but none of these features are denitive [49, 50]. There are four validated methods for the denitive identication of BCG. These four methods are phage typing [51], HPLC [52], restriction fragment length polymorphism analysis with use of the insertion element IS1081 as a probe (i.e., IS1081 ngerprinting) [53], and amplication of a specic region containing the MPTR by PCR followed by REA [31]. Each of these methods has advantages and disadvantages. Phage typing is laborious and not widely available. HPLC is rapid and easy to perform, but it requires a fresh isolate on proper medium as

well as specialized and expensive equipment. IS1081 ngerprinting is more laborious, requiring careful isolation of DNA from a large bacterial culture followed by Southern blot hybridization with a specic probe. This technique is generally not available to clinical microbiology laboratories. Amplication of MPTR by PCR and REA only requires a small specimen from a clinical isolate, has been applied to heat-killed cultures [31], and may be directly applicable to smear-positive clinical specimens, as has been reported for other PCR-based methods for strain differentiation [54]. Rationale for the working denition of disseminated BCG disease. The working denition of disseminated BCG disease

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID

CID 1997;24 (June)

Disseminated BCG Disease

1143

Table 4. Summary of data on nine probable cases of disseminated BCG disease that were reported from 1980 through 1995.
Case no. [reference]
29 [22] 30 [23] 31 [24] 32 [25] 33 [13] 34 [26] 35 [13] 36 [27] 37 [28]

Country: patient/report
Ethiopia/Israel Algeria/France Haiti/France Saudi Arabia/Saudi Arabia Chile/Chile South Africa/South Africa Chile/Chile France/United Kingdom United Kingdom/United Kingdom

Age/sex
3 mo/F 32 y/M 4 mo/M 9 mo/F 5 mo/M 4 mo/M 10 mo/M 1 y/F 4 mo/F

Immune defect
AIDS AIDS AIDS SCID CGD CGD CMI Transient CMI Omenns disease

Conrmed site(s) of dissemination


R LN R LN NR Skin, multiple bone sites D LN R LN D LN D LN Thigh abscess (at vaccination site)

Systemic syndrome
Fever, failure to thrive, HSM, anemia Fever, weight loss, diarrhea, SM Failure to thrive, LAD, HSM Fever, failure to thrive, diarrhea NR Failure to thrive, HSM, LAD NR Fever, weight loss, LAD Fever, failure to thrive, LAD

Antimicrobial therapy
INH, Rif, Stm INH, Rif, Ethi, PZA NR NR INH, Rif, Stm INH, Rif, Eth, PZA INH, Rif INH, Eth, Stm, Clof INH, Rif, Amik

Outcome
Died Died NR Died Died Died Died Survived Survived

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

NOTE. Amik amikacin; CGD chronic granulomatous disease; Clof clofazimine; CMI cell-mediated immune defect; D distant; Eth ethambutol; Ethi ethionamide; HSM hepatosplenomegaly; INH isoniazid; LAD lymphadenopathy; LN lymph node; NR not reported; PZA pyrazinamide; R regional; Rif rifampin; SCID severe combined immunodeciency; SM splenomegaly; Stm streptomycin.

(table 2) requires the following: a culture positive for BCG (the identication of which has been conrmed by biochemical methods at least); demonstration of dissemination by either a positive blood or bone marrow culture or evidence of infection at two or more anatomic sites beyond the region of vaccination; and signs and symptoms consistent with mycobacterial disease. This working denition was developed before our literature search as a tool to identify only denite cases. We used the literature on disseminated Mycobacterium avium complex disease [55] and other disseminated mycobacterial diseases [56] to develop the working denition of disseminated BCG disease. Some researchers have used the terms disseminated or generalized to refer to any locus of infection beyond the region of vaccination. We believe that there are important distinctions between extraregional localized disease (e.g., isolated osteitis or lymphadenitis) and disseminated disease involving multiple organ systems. For example, disseminated BCG disease occurs almost exclusively in immunocompromised hosts, is frequently associated with a negative tuberculin test, is not associated with histological ndings of well-formed granulomas [57], responds poorly to therapy, and is frequently fatal. In contrast, generalized BCG lymphadenitis occurs in immunocompetent hosts (for whom results of tuberculin tests are normal), provokes a typical histological response [58, 59], and can sometimes resolve without therapy [34]. The third requirement for our working denition is a systemic syndrome consistent with mycobacterial disease. This requirement is intended to distinguish disseminated BCG disease from the asymptomatic dissemination of BCG that occurs after vaccination of infants with an intact immune system. In fact, dissemination of BCG is a normal sequela of BCG

vaccination [60]. In 1956, Gormsen [61] performed autopsies on BCG-vaccinated infants and children who died of unrelated causes; histological examination of tissues demonstrated granulomas in many distant organs, including liver, lungs, spleen, and kidneys. Organisms were found up to 3 years after vaccination without evidence of clinical disease. This work was effectively reproduced by Trevenen and Pagtakhan [62] in 1982. Treatment of disseminated BCG disease. There is pessimism in the historic literature regarding the treatment of disseminated BCG disease in immunocompromised hosts. In 1972, Sicevic [63] wrote that it is generally known that antitubercular drugs have no effect on the treatment of generalized BCG tuberculosis in immunodecient children. In 1977, Genin et al. [64] referred to the inevitable progression to death within 6 months in immunocompromised patients with generalized disease in spite of antimicrobial therapy. There is little published information about regimens that are useful in the treatment of disseminated BCG disease that occurs after vaccination. However, there are therapeutic precedents established for other types of infection caused by BCG. Therapy for disseminated disease following intravesical instillation of BCG should include isoniazid, rifampin, and a corticosteroid [65, 66]. Isoniazid, rifampin, and erythromycin have been used in the treatment of suppurative lymphadenitis at the site of BCG vaccination [67, 68]. Experience with treatment of infection due to non BCG strains of M. bovis is limited, but this therapy is another obvious model for disseminated BCG disease. Ten patients with M. bovis infection in a Spanish review [69] all received therapy with isoniazid, rifampin, and ethambutol. Nine patients were cured and had no relapses, and one patient died of other causes.

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID

1144

Talbot et al.

CID 1997;24 (June)

In another retrospective review [70], most M. bovis isolates from 73 patients were sensitive to rst-line antituberculous drugs (except pyrazinamide, to which M. bovis is uniformly resistant), and nearly all patients responded to therapy. The antimycobacterial regimens used to treat patients whose cases were identied in our review are listed in tables 3 and 4. Isoniazid, rifampin, ethambutol, and streptomycin were most commonly used. It is striking that 70% of patients died even when their cases were aggressively managed. Plausible explanations for this high mortality rate include associated immunodeciencies, delay in diagnosis or treatment (case 3), initial treatment with pyrazinamide to which BCG is uniformly resistant (cases 18 and 22), and the emergence of resistance to therapy (case 24) [63]. The high mortality rate may be a result of reporting bias. Experience in the treatment of patients with AIDS and other mycobacterial diseases may provide principles for the treatment of immunocompromised patients with disseminated BCG disease. Poor drug absorption, drug interactions, and frequent adverse drug reactions have been observed to complicate therapy for mycobacterial infections in patients with AIDS [71 74]. Prolonged therapy is recommended for patients with AIDS and M. tuberculosis [75] or M. avium complex infections [76]. Implications for strategies for BCG vaccination. Vaccination strategies attempt to balance risk and benet. The benet of BCG immunization against M. tuberculosis infection has been the subject of much controversy and is beyond the scope of this article. A summary of trials on the efcacy of BCG vaccine has recently been published [77]. Virtually nothing is known about the efcacy of BCG vaccine for infants with HIV infection. However, HIV infection greatly increases the incidence of tuberculosis, so even a small degree of efcacy would have a major impact [78]. In addition to the effects on tuberculosis, BCG vaccine may also prevent other mycobacterial diseases, including cervical lymphadenitis due to atypical mycobacteria [79, 80] and Hansens disease [81]. The risks associated with BCG vaccination include local complications, extraregional localized disease, and disseminated BCG disease. The mortality attributable to disseminated BCG disease may be limited, since most patients have fatal underlying diseases. However, because of the emergence of HIV infection, the incidence of disseminated disease is probably greater than that (1.56 cases per 1 million BCG-vaccinated individuals) found by Lotte et al. [30]. Current recommendations regarding BCG vaccination vary, reecting different risk/benet settings. In settings where prenatal screening for HIV infection is not available and the risk of tuberculosis is high, the World Health Organization [82] recommends vaccinating all children not symptomatic for HIV infection. In developed countries, prenatal screening for HIV infection is becoming routine. The Advisory Committee on Immunization Practices in the United States [83] emphasizes withholding BCG vaccination from HIV-infected patients regardless of symptoms in regions in which the risk of tuberculosis is low.

The American Academy of Pediatrics [84] recommends that a child who receives BCG vaccination but does not have a positive reaction to the tuberculin test be revaccinated. The benet of this second BCG vaccination for prevention of tuberculosis is not established, but our review indicates that there are risks associated with this practice. Patients with severe immunodeciencies (including AIDS and severe combined immunodeciency) are often anergic and would be selected for repeated vaccination by this policy. Three cases of disseminated BCG disease (nos. 24, 30, and 36) developed after revaccination because of a negative tuberculin test. Case reporting. Conrmed or suspected cases of disseminated BCG disease should be reported in the medical literature and to the appropriate authorities. Because disseminated BCG disease is caused by an adverse drug reaction, cases should be reported to vaccine manufacturers (in the United States, Organon Teknika, Durham, NC [800-842-3220]) and the Vaccine Adverse Event Reporting System (800-822-7967). The corresponding author of this article (R.F.) would be pleased to collaborate in the denite identication of possible BCG isolates.

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

Acknowledgments

The authors thank Margaret M. Floyd (Centers for Disease Control and Prevention) for performing HPLC on our isolate, Mario Cesar Gomes for technical assistance, and Winifred Ann MeekerOConnell for her thoughtful review of the manuscript.

Note Added in Proof

A new method of BCG identication was applied to cultures that were killed using ethanol and shipped without hazard at room temperature [85]. This method is available to clinicians worldwide for conrmation of BCG complications.

References 1. Lugosi L. Theoretical and methodological aspects of BCG vaccine from the discovery of Calmette and Guerin to molecular biology. A review. Tuber Lung Dis 1992; 73:252 61. 2. Kroger L, Korppi M, Brander E, et al. Osteitis caused by bacille Calmette Guerin vaccination: a retrospective analysis of 222 cases. J Infect Dis 1995; 172:574 6. 3. Edwards KM, Kernodle DS. Possible hazards of routine bacille CalmetteGuerin immunization in human immunodeciency virus infected children. Pediatr Infect Dis J 1996; 15:836 8. 4. Besnard M, Sauvion S, Offedro C, et al. Bacillus Calmette-Guerin infection after vaccination of human immunodeciency virus-infected children. Pediatr Infect Dis J 1993; 12:993 7. 5. Armbruster C, Junker W, Vetter N, Jaksch G. Disseminated bacille Calmette-Guerin infection in an AIDS patient 30 years after BCG vaccination. J Infect Dis 1990; 162:1216. 6. ten Dam HG. BCG vaccination and HIV infection. Bull Int Union Tuberc Lung Dis 1990; 65:38 9. 7. Houde C, Dery P. Mycobacterium bovis sepsis in an infant with human immunodeciency virus infection. Pediatr Infect Dis J 1988; 7:810 1.

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID

CID 1997;24 (June)

Disseminated BCG Disease

1145

8. Ninane J, Grymonprez A, Burtonboy G, Francois A, Cornu G. Disseminated BCG in HIV infection. Arch Dis Child 1988; 63:1268 9. 9. Hulin A, Lefevre P, Rieux D, Desbordes JM. A propos dun cas de becegite generalisee mortelle chez un adulte suspect de decit immunitaire acquis (SIDA). Medecine dAfrique Noire 1986; 33:293 300. 10. Centers for Disease Control. Disseminated Mycobacterium bovis infection from BCG vaccination of a patient with acquired immunodeciency syndrome. MMWR Morb Mortal Wkly Rep 1985; 34(16):227 8. 11. Romanus V, Fasth A, Tordai P, Wiholm BE. Adverse reactions in healthy and immunocompromised children under six years of age vaccinated with the Danish BCG vaccine, strain Copenhagen 1331: implications for the vaccination policy in Sweden. Acta Paediatr 1993; 82:1043 52. 12. Abramowsky C, Gonzalez B, Sorensen RU. Disseminated Bacillus Calmette-Guerin infections in patients with primary immunodeciencies. Am J Clin Pathol 1993; 100:52 6. 13. Gonzalez B, Moreno S, Burdach R, et al. Clinical presentation of bacillus Calmette-Guerin infections in patients with immunodeciency syndromes. Pediatr Infect Dis J 1989; 8:201 8. 14. Hodsagi M, Uhereczky G, Kiraly L, Pinter E. BCG dissemination in chronic granulomatous disease (CGD). Dev Biol Stand 1986; 58:339 46. 15. Jeppsson O, Petrini B, Andersson J, Heurlin N, Malm G. Defective handling of mycobacteria. Lancet 1988; 2:570. 16. Fischer A, Virelizier JL, Grisscelli C, Durandy A, Nezelof C, Trung PH. Defective monocyte functions in a child with fatal disseminated BCG infection. Clin Immunol Immunopathol 1980; 17:296 306. 17. Mackay A, Alcorn MJ, Macleod IM, et al. Fatal disseminated BCG infection in an 18-year-old boy. Lancet 1980; 2:1332 3. 18. Lachaux A, Descos B, Mertani A, Souillet G, Gilly J, Hermier M. Infection generalisee a BCG devolution favorable chez un nourrisson de 3 mois sans decit immunitaire reconnu. Arch Fr Pediatr 1986; 43:807 9. 19. Kallenius G, Moller E, Ringden O, Strandvik B, Sundelin P. The rst infant to survive a generalized BCG infection. Acta Paediatr Scand 1982; 71:161 5. 20. Catanzaro A, Melish ME, Minkoff DI. Disseminated BCG infection. J Pediatr 1981; 99:268 71. 21. Perelman R, Danis F, Nathanson M, Lafay F, Garcia J, Fischer A. A propos dun cas de becegite generalisee mortelle sans decit immunitaire apparent. Sem Hop Paris 1980; 56:480 3. 22. Marks K, Amitai Y, Engelhard D, Kori M, Maayan S. Mycobacterium bovis lymphadenitis complicating BCG immunization in an infant with symptomatic HIV-1 infection. Isr J Med Sci 1993; 29:381 2. 23. Boudes P, Sobel A, Deforges L, Leblic E. Disseminated M. bovis infection from BCG vaccination and HIV infection. JAMA 1989; 262:2386. 24. Vilmer E, Fischer A, Griscelli C, et al. Possible transmission of a human lymphotropic retrovirus (LAV) from mother to infant with AIDS. Lancet 1984; 2:229 30. 25. Hugosson C, Har H. Disseminated BCG-osteomyelitis in congenital immunodeciency. Pediatr Radiol 1991; 21:384 5. 26. Smith PAG, Wittenberg DF. Disseminated BCG infection in a child with chronic granulomatous disease. S Afr Med J 1984; 65:821 2. 27. Webster ADB, Goolamali SK. BCGosis. J R Soc Med 1981; 74:163 5. 28. Heyderman RS, Morgan G, Levinsky RJ, Strobel S. Successful bone marrow transplantation and treatment of BCG infection in two patients with severe combined immunodeciency. Eur J Pediatr 1991; 150:477 80. 29. Lotte A, Wasz-Hockert O, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications: estimates for the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res 1984; 21:107 93. 30. Lotte A, Wasz-Hockert O, Poisson N, et al. Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc 1988; 63:47 59. 31. Frothingham R. Differentiation of strains in Mycobacterium tuberculosis complex by DNA sequence polymorphisms, including rapid identication of M. bovis BCG. J Clin Microbiol 1995; 33:840 4.

32. Glickman SE, Kilburn JO, Butler WR, Ramos LS. Rapid identication of mycolic acid patterns of mycobacteria by high-performance liquid chromatography using pattern recognition software and a mycobacterium library. J Clin Microbiol 1994; 32:740 5. 33. Nolte FS, Metchock B. Mycobacterium. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of clinical microbiology. 6th ed. Washington, DC: American Society for Microbiology. 1995: 400 37. 34. Katzir Z, Okon E, Ludmirski A, Sherman Y, Haas H. Generalized lymphadenitis following BCG vaccination in an immunocompetent 12-yearold boy. Eur J Pediatr 1984; 141:165 7. 35. Pedersen FK, Engbaek HC, Hertz H, Vergmann B. Fatal BCG infection in an immunocompetent girl. Acta Paediatr Scand 1978; 67:519 23. 36. Smith E, Thybo S, Bennedsen J. Infection with Mycobacterium bovis in a patient with AIDS: a late complication of BCG vaccination. Scand J Infect Dis 1992; 24:109 10. 37. Lumb R, Shaw D. Mycobacterium bovis (BCG) vaccination: progressive disease in a patient asymptomatically infected with the human immunodeciency virus. Med J Aust 1992; 156(4):286 7. 38. Janier M, Moulonguet I, Casin I, et al. Abces sous-cutane a Mycobacterium bovis variete BCG chez un patient seropositif VIH. Ann Dermatol Venereol 1989; 116:35 7. 39. Reynes J, Perez C, Lamaury I, Janbon F, Bertrand A. Bacille CalmetteGuerin adenitis 30 years after immunization in a patient with AIDS. J Infect Dis 1989; 160:727. 40. Blondon H, Guez T, Paul G, Truffot-Pernot CH, Sicard D. Adenite a BCG 6 ans apres la vaccination au cours dun SIDA. Presse Med 1991; 20: 1091. 41. Nousbaum JB, Garre M, Boles JM, Garo B, Larzul JJ. Deux manifestations inhabituelles dune infection par le virus LAV-HTLV III: BCG-ite et varicelle pulmonaire. Rev Pneumol Clin 1986; 42:310 1. 42. von Reyn CF, Clements CJ, Mann JM. Human immunodeciency virus infection and routine childhood immunisation. Lancet 1987; 2:669 72. 43. Carswell M. BCG immunization in the children of HIV-positive mothers. AIDS 1987; 1:258. 44. Msellati P, Dabis F, Lepage P, Hitimana DG, van Goethem C, van de Perre P. BCG vaccination and pediatric HIV infection Rwanda, 1988 1990. MMWR Morb Mortal Wkly Rep 1991; 40(48):833 6. 45. Lallemant-Le Coeur S, Lallemant M, Cheynier D, Nzingoula S, Drucker J, Larouze B. Bacillus Calmette-Guerin immunization in infants born to HIV-1-seropositive mothers. AIDS 1991; 5:195 9. 46. Blanche S, Le Deist F, Fischer A, et al. Longitudinal study of 18 children with perinatal LAV/HTLV III infection: attempt at prognostic evaluation. J Pediatr 1986; 109:965 70. 47. OBrien KL, Ruff AJ, Louis MA, et al. Bacillus Calmette-Guerin complications in children born to HIV-1-infected women with a review of the literature. Pediatrics 1995; 95:414 8. 48. Marsh BJ, von Reyn CF, Edwards J, Tosteson A, Arbeit RD. The risks and benets of childhood BCG immunization among adults with AIDS [abstract 152]. Clin Infect Dis 1996; 23:887. 49. Wayne LG. Microbiology of tubercle bacilli. Am Rev Respir Dis 1982; 125(suppl):31 41. 50. Wayne LG, Kubica GP. The mycobacteria. In: Sneath PHA, Holt JG, eds. Bergeys manual of systemic bacteriology. Vol 2. Baltimore: Williams & Wilkins, 1986:1435 57. 51. Jones WD. Differentiation of known strains of BCG from isolates of Mycobacterium bovis and Mycobacterium tuberculosis by using mycobacteriophage 33D. J Clin Microbiol 1975; 1:391 2. 52. Floyd MM, Silcox VA, Jones WD, Butler WR, Kilburn JO. Separation of Mycobacterium bovis BCG from Mycobacterium tuberculosis and Mycobacterium bovis by using high-performance liquid chromatography of mycolic acids. J Clin Microbiol 1992; 30:1327 30. 53. van Soolingen D, Hermans PWM, de Haas PEW, van Embden JDA. Insertion element IS1081-associated restriction fragment length poly-

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID

1146

Talbot et al.

CID 1997;24 (June)

54.

55. 56.

57.

58.

59.

60.

61.

62. 63. 64. 65. 66.

67.

68.

69.

70.

morphisms in Mycobacterium tuberculosis complex species: a reliable tool for recognizing Mycobacterium bovis BCG. J Clin Microbiol 1992; 30:1772 7. Telenti A, Imboden P, Marchesi F, Schmidheini T, Bodmer T. Direct, automated detection of rifampin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 1993; 37:2054 8. Horsburgh CR. Mycobacterium avium complex infection in the acquired immunodeciency syndrome. N Engl J Med 1991; 324:1332 8. Snider DE, Hopewell PC, Mills J, Reichman LB. Mycobacterioses and the acquired immunodeciency syndrome. Am Rev Respir Dis 1987; 136:492 6. Kumar PV, Banani SA. Fine needle aspiration ndings in generalized postCalmette-Guerin bacillus lymphadenitis presenting as an abdominal mass. Acta Cytol 1994; 38:165 8. Cotran RS, Kumar V, Robbins SL. Inammation and repair. In: Cotran RS, Kumar V, Robbins SL, eds. Robbins pathologic basis of disease. 4th ed. Philadelphia: WB Saunders, 1991:39 71. Wallace RJ, OBrien R, Glassroth J, Raleigh J, Dutt A. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am Rev Respir Dis 1990; 142:940 53. Vogelsang TM, Wetteland P. Dispersion and viability of BCG after intradermal injection in the guinea pig. Acta Pathol Microbiol Scand 1960; 48:169 75. Gormsen H. On the occurrence of epithelioid granulomas in the organs of BCG-vaccinated human beings. APMIS 1956; 39(suppl 111):117 20. Trevenen CL, Pagtakhan RD. Disseminated tuberculoid lesions in infants following BCG vaccination. Can Med Assoc J 1982; 127:502 4. Sicevic S. Generalized BCG tuberculosis with a fatal course in two sisters. Acta Paediatr Scand 1972; 61:178 84. Genin C, Touraine JL, Berger F, et al. B.C.Gite generalisee dans un decit immunitaire mixte et grave. Arch Fr Pediatr 1977; 34:639 48. Koukol SC, DeHaven JI, Riggs DR, Lamm DL. Drug therapy of bacillus Calmette-Guerin sepsis. Urol Res 1995; 22(6):373 6. Steg A, Leleu C, Debre B, Boccon-Gibod L, Sicard D. Systemic bacillus Calmette-Guerin infection, BCGitis, in patients treated by intravesical bacillus Calmette-Guerin therapy for supercial bladder cancer. Eur Urol 1989; 16(3):161 4. Caglayan S, Yegin O, Kayran K, Timocin N, Kasirga E, Gun M. Is medical therapy effective for regional lymphadenitis following BCG vaccination? Am J Dis Child 1987; 141:1213 4. De Souza SGR, Sant Anna CC, Lapa e Silva JR, Mano DB, Bethlem NM. Intradermal BCG vaccination complications analysis of 51 cases. Tubercle 1983; 64:23 37. Sauret J, Jolis R, Ausina V, Castro E, Cornudella R. Human tuberculosis due to Mycobacterium bovis: report of 10 cases. Tuber Lung Dis 1992; 73:388 91. Dankner WM, Waecker NJ, Essey MA, Moser K, Thompson M, Davis CE. Mycobacterium bovis infections in San Diego: a clinicoepidemio-

71.

72.

73.

74. 75.

76.

77.

78.

79.

80. 81.

82.

83.

84.

85.

logic study of 73 patients and a historical review of a forgotten pathogen. Medicine (Baltimore) 1993; 72:11 37. Gordon SM, Horsburgh CR Jr, Peloquin CA, et al. Low serum levels of oral antimycobacterial agents in patients with disseminated Mycobacterium avium complex disease. J Infect Dis 1993; 168:1559 62. Berning SE, Huitt GA, Iseman MD, Peloquin CA. Malabsorption of antituberculosis medications by a patient with AIDS [letter]. N Engl J Med 1992; 327:1817 8. Small PM, Schecter G, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeciency virus infection. N Engl J Med 1991; 324:289 94. Engelhard D, Stutman HR, Marks MI. Interaction of ketoconazole with rifampin and isoniazid. N Engl J Med 1984; 311:1681 3. Advisory Council for the Elimination of Tuberculosis. Initial therapy for tuberculosis in the era of multidrug resistance. MMWR Morb Mortal Wkly Rep 1993; 42(RR-7):1 8. Masur H. Recommendations on prophylaxis and therapy for disseminated mycobacterium avium complex disease in patients infected with the human immunodeciency virus. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex. N Engl J Med 1993; 329:898 904. Colditz GA, Brewer TF, Berkey CS, et al. Efcacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 1994; 271:698 702. Gutman LT, Moye J, Zimmer B, Tian C. Tuberculosis in human immunodeciency virus-exposed or -infected United States children. Pediatr Infect Dis J 1994; 13:963 8. Romanus V, Hallander HO, Wahlen P, Olinder-Nielsen AM, Magnusson PHW, Juhlin I. Atypical mycobacteria in extrapulmonary disease among children. Incidence in Sweden from 1969 to 1990, related to changing BCG-vaccination coverage. Tuber Lung Dis 1995; 76:300 10. Katila ML, Brander E, Backman A. Neonatal BCG vaccination and mycobacterial cervical adenitis in childhood. Tubercle 1987; 68:291 6. Stanley SJ, Howland C, Stone MM, Sutherland I. BCG vaccination of children against leprosy in Uganda: nal results. J Hyg (Lond) 1981; 87(2):233 48. World Health Organization. Expanded programme on immunization: joint WHO/UNICEF statement on immunization and AIDS. Wkly Epidemiol Rec 1987; 62:53 4. Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. The role of BCG vaccine in the prevention and control of tuberculosis in the United States. MMWR Morb Mortal Wkly Rep 1996; 45(RR-4):1 18. Committee on Infectious Diseases of the American Academy of Pediatrics. Tuberculosis. In: Peter G, Halsey NA, Marcuse EK, Pickering LK, eds. 1994 Red book: report of the committee on infectious diseases. 23rd ed. Elk Grove Village, Illinois: American Academy of Pediatrics, 1994: 480 500. Talbot EA, Williams DL, Frothingham R. PCR identication of Mycobacterium bovis BCG. J Clin Microbiol 1997; 35:566 9.

Downloaded from http://cid.oxfordjournals.org/ by guest on February 17, 2013

/ 9c2f$$ju20

05-06-97 20:09:15

cida

UC: CID