Second Episode of Tuberculosis in an HIV-infected Child: Relapse or Reinfection?

Case Reports

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01 Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26: 781–803. 02 Cohen MS, Isturiz RE, Malech HL et al. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med 1981; 71: 59–66. 03 Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect Dis 1996; 23: 608–615. 04 Roilides E, Holmes A, Blake C, Venzon D, Pizzo PA, Walsh TJ. Antifungal activity of elutriated human monocytes against Aspergillus fumigatus hyphae: enhancement by granulocytemacrophage colony-stimulating factor and interferon-gamma. J Infect Dis 1994; 170: 894–899. 05 Smith DL, Rommel F. A rapid micro method for the simultaneous determination of phagocytic-microbiocidal activity of human peripheral blood leukocytes in vitro. J Immunol Methods 1977; 17: 241–247. 06 Kamani NR, Douglas SD. Disorders of the mononuclear phagocytic system. In: E. Richard Stiehm (ed). Immunologic Disorders in Infants and Children, 4th edition. WB Saunders, 1996: 469–489. 07 Uchiyama N, Greene GR, Warren BJ, Morozumi PA, Spear GS, Galant SP. Possible monocyte killing defect in familial atypical mycobacteriosis. J Pediatr 1981; 98: 785–788. 08 Yamazaki M, Yasui K, Kawai H, Miyagawa Y, Komiyama A, Akabane T. A monocyte disorder in siblings with chronic candidiasis. A combined abnormality of monocyte mobility and phagocytosis-killing ability. Am J Dis Child 1984; 138: 192–196. 09 Ridgway D, Wolff LJ, Wall M, Borzy MS, Kirkpatrick CH. Indomethacin-sensitive monocyte killing defect in a child with disseminated atypical mycobacterial disease. J Clin Immunol 1991; 11: 357–362. 10 Newport MJ, Huxley CM, Huston S et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996; 335: 1941–1949.

11 de Jong R, Altare F, Haagen IA et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 1998; 280: 1435–1438. 12 Baldwin GC, Fleischmann J, Chung Y, Koyanagi Y, Chen IS, Golde DW. Human immunodeficiency virus causes mononuclear phagocyte dysfunction. Proc Natl Acad Sci USA 1990; 87: 3933–3937. 13 Estevez ME, Sen L, Bachmann AE, Pavlovsky A. Defective function of peripheral blood monocytes in patients with Hodgkin’s and non-Hodgkin’s lymphomas. Cancer 1980; 46: 299–302. 14 Sponseller PD, Malech HL, McCarthy EF Jr, Horowitz SF, Jaffe G, Gallin JI. Skeletal involvement in children who have chronic granulomatous disease. J Bone Joint Surg [Am] 1991; 73: 37–51. 15 Pasic S, Abinun M, Pistignjat B et al. Aspergillus osteomyelitis in chronic granulomatous disease: treatment with recombinant gamma-interferon and itraconazole. Pediatr Infect Dis J 1996; 15: 833–834. 16 Kline MW, Bocobo FC, Paul ME, Rosenblatt HM, Shearer WT. Successful medical therapy of Aspergillus osteomyelitis of the spine in an 11-year-old boy with chronic granulomatous disease. Pediatrics 1994; 93: 830–835. 17 Giles FJ. Monocyte-macrophages, granulocyte-macrophage colonystimulating factor, and prolonged survival among patients with acute myeloid leukemia and stem cell transplants. Clin Infect Dis 1998; 26: 1282–1289. 18 Rodriguez-Adrian LJ, Grazziutti ML, Rex JH, Anaissie EJ. The potential role of cytokine therapy for fungal infections in patients with cancer: is recovery from neutropenia all that is needed? Clin Infect Dis 1998; 26: 1270–1278. 19 Bodey GP, Anaissie E, Gutterman J, Vadhan-Raj S. Role of granulocyte-macrophage colony-stimulating factor as adjuvant treatment in neutropenic patients with bacterial and fungal infection. Eur J Clin Microbiol Infect Dis 1994; 13(Suppl 2): S18–S22. 20 Ruef C, Coleman DL. Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness. Rev Infect Dis 1990; 12: 41–62.

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Second Episode of Tuberculosis in an HIV-infected Child: Relapse or Reinfection? H. S. Schaaf*1, R. P. Gie1, A. van Rie1, H. I. Seifart2, P. D. van Helden3 and M. F. Cotton1 1 Department of Paediatrics and Child Health, 2Department of Pharmacology and Department of Medical Biochemistry, University of Stellenbosch, Tygerberg, South Africa

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We report a case of an HIV-infected child with a second episode of tuberculosis 22 months after completing antituberculosis treatment. DNA fingerprinting of organisms from both episodes showed an identical strain of Mycobacterium tuberculosis. We believe this to be the first case of confirmed relapsed tuberculosis in an HIV-infected child, and suggest that a longer course of antituberculosis treatment be given to such children. © 2000 The British Infection Society

Introduction * Please address all correspondence to: H. S. Schaaf, Department of Paediatrics and Child Health, University of Stellenbosch. Francie van Zijl Avenue, Clinical Building, Room 2077/PO Box 19063, Tygerberg 7505, Soth Africa. Accepted for publication 22 March 2000. © 2000 The British Infection Society

Mycobacterium tuberculosis is a common opportunistic infection in patients infected with the human immunodeficiency virus (HIV). Treatment of tuberculosis in HIV-infected patients is usually effective, but the optimal duration of therapy is still uncertain.1,2 Poor response to treatment and relapse after completion have been reported in children.3–5 Our report describes an

Case Reports HIV-infected child with disseminated tuberculosis, treated with high-dose, directly observed short-course chemotherapy (SCC) and presenting again 22 months after completion of treatment with confirmed pulmonary TB. DNA fingerprinting of organisms from both episodes showed an identical strain of M. tuberculosis, suggesting relapse.

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(amoxicillin/clavulanate) was initiated with little improvement. After 2 weeks his follow-up chest radiograph showed increasing paratracheal and hilar adenopathy with RML opacification. Bronchoscopy revealed glandular indentation of the trachea. A computed tomography (CT) scan of the chest confirmed the lymphadenopathy and parenchymal consolidation of the RML with additional cavitation and fibrosis. Cultures from earswabs and bronchial lavage yielded Pseudomonas aeruginosa, treated with

Case Report A 19-month-old boy was initially referred to a tertiary care facility in the Western Cape province of South Africa with fever, vomiting and loss of appetite for 4 days. There was no history of coughing or weight loss, but he had bilateral chronic otorrhoea from 4 months of age. There was no history of household tuberculosis contact. Immunizations were up to date and included a BCG at birth. On the day of admission his level of consciousness deteriorated. On examination he was acutely ill. His Glasgow coma score was 12/15. His weight and length was below the third centile (NCHS centile charts for age). He had general lymphadenopathy, oral thrush, tachypnoea, hepatosplenomegaly and bilateral otorrhoea. Meningeal irritation was present without focal neurological signs. The tuberculin skin test (Mantoux test) was 20 mm. There was mediastinal lymphadenopathy and a cavity in an opacified right middle lobe on the chest radiograph. Cerebrospinal fluid (CSF) was indicative of tuberculous meningitis with a raised protein (2.36 g/l), a decreased glucose (1.6 mmol/l), 140 lymphocytes per mm3 and 13 polymorphs per mm3 being present. Computed tomography (CT) of the brain showed basal enhancement and hydrocephalus. The diagnosis of disseminated tuberculosis was confirmed, with M. tuberculosis cultured from the CSF and gastric aspirate. The M. tuberculosis isolate was susceptible to isoniazid. HIV infection was confirmed by three HIV enzyme-linked immunosorbent assay tests. The CD4 count at time of diagnosis was 1148 cells/mm3 (29%). He was classified as C1 according to the revised CDC–a paediatric HIV classification.6 His mother was HIV-infected but tuberculosis could not be confirmed. Examination of household members by sputum examination and chest radiography failed to find the index case. The child was treated in hospital for 6 months by daily administration of four antituberculosis drugs (isoniazid 20 mg/kg, rifampin 20 mg/kg, pyrazinamide 40 mg/kg and ethionamide 20 mg/kg).7 He received a total of 170 doses. He gained weight and was clinically well at discharge. The chest radiograph was normal at that time and remained so for the next 18 months. No antiretroviral drugs were prescribed due to cost constraints. Twenty-two months after completing his TB treatment, he again presented with fever and abdominal pain. He had lost weight over a 1-month period but was not coughing. There was no history of tuberculosis contact in the household or any known community index case. The mother had died a week previously from progressive multifocal leucoencephalopathy. At the time of death she had no proof of active TB and her chest radiograph was normal. On examination the child had general lymphadenopathy, otorrhoea, oral thrush and ulcers, hepatomegaly and impaired speech development. Chest radiography showed opacification of the right middle lobe (RML). C-reactive protein (101 ␮g/ml) and the white cell count (18109/l) were raised. Blood culture and the direct immunofluorescence test for Pneumocystis carinii was negative. The Mantoux test was non-reactive. CD4 count was 16 cells/mm3 (1%) and he was now classified as C3.6 Antibiotic treatment

Figure 1. RFLP analysis of M. tuberculosis isolates. (1) Isolates from gastric aspirate and CSF collected during the first episode. (2) Isolates from gastric aspirate and bronchial aspirate collected during the second episode. R, reference strain MTB 14323.

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amikacin and piperacillin. Mycobacterium tuberculosis, susceptible to isoniazid and rifampin, was cultured from two bronchial aspirates and two gastric aspirates. CSF examination was completely normal. Isolates from both episodes were genotyped by restriction fragment length polymorphism (RFLP) analysis using the internationally standardized method (IS6110-3⬘)8 and three additional probes (ECL-labelled IS6110-5⬘, DRr probe for PvuII digests and 32 P-labelled MTB484(1) probe for Hinf1 digests).9 To exclude laboratory contamination, two isolates of both episodes of tuberculosis were analysed. All isolates had exactly the same DNA fingerprint pattern on RFLP analysis, suggesting reactivation of the M. tuberculosis strain responsible for the first tuberculosis episode (Fig. 1). Isoniazid absorption and sequential serum levels were determined after a dose of 150 mg (13.3 mg/kg) by high-performance liquid chromatography (HPLC).10 Absorption was delayed and serum levels peaked at 3 h post-administration. Isoniazid serum levels within the time period of 2–5 h post-administration were all within the therapeutic range and above the minimal inhibitory concentration (serum levels 2.9–1.3 ␮g/ml). The child was again treated with isoniazid, rifampin and pyrazinamide and responded well with good weight gain. The chest radiograph improved. He was treated as an outpatient at the local authority health clinic with directly observed therapy.

Discussion As far as we could determine, this is the first case of relapse of tuberculosis after cure in a HIV-infected child in whom the RFLP patterns of the M. tuberculosis retrieved from both episodes were identical. In HIV-infected adults both reactivation and reinfection have been documented by RFLP analysis of M. tuberculosis.11 An interesting feature of this child is that he recovered fully from the tuberculous meningitis and that relapse had occurred in the lung. At initial diagnosis the chest radiograph showed a cavity in the right middle lobe which was thought to have healed completely. Nevertheless, the CT scan at the time of relapse showed fibrosis and a small residual cavity in the right middle lobe, which could have been the source of the reactivated M. tuberculosis. We speculate that the drug penetration into the cavity may have been ineffective, resulting in viable organisms remaining in the wall. We have previously observed that in HIV-negative children treated for pulmonary TB but with bronchiectasis, we were able to reculture the M. tuberculosis from the resected lobe (personal communication: R. P. Gie). A declining CD4 T-cell count may have precipitated the reactivation. Since the index case for the two episodes of tuberculosis could not be identified, it is possible that reinfection with the same strain occurred through contact with an unidentified source case. However, given the exhaustive contact investigation performed, we consider this possibility highly unlikely. Other possible causes for relapse were also considered. Susceptibility testing was done on both occasions and the M. tuberculosis organism was sensitive to isoniazid and rifampicin, excluding resistance. It has been suggested that impaired absorption of antituberculosis agents could play a role in treatment failure or relapse of TB in HIV-infected patients due to associated gastrointestinal conditions.12,13 In our patient this was not the case, since the absorption and sequential serum levels of isoniazid were appropriate. The duration of anti-tuberculosis treatment in HIV-infected patients has been widely discussed, but no consensus has been reached.1,2,14 Several authors have shown similar relapse rates in

HIV-positive and HIV-negative adults with TB if isoniazid and rifampin were included in the SCC.15,16 Mortality rates were always higher in the dually-infected groups.15,16 Others, however, have documented a considerable increase in relapse rate of TB after a median of 30 months’ follow-up in HIV-infected adults treated for only 6 months compared to a 9 month course (24% vs. 3.4%).17 Espinal et al.3 found that six of 21 (29%) of HIV-infected children with TB failed SCC treatment as compared with five of 156 (3%) HIV-negative children. Jeena et al.5 documented a higher mortality and a slower recovery rate of TB in HIV-infected children as compared with HIV-negative children. The present patient is one of 14 HIV-infected children with culture proven TB reported previously.4 He is the fifth child in whom a positive culture of M. tuberculosis was obtained 4 or more months after starting SCC which included isoniazid and rifampicin.4 Tuberculous meningitis is a severe extrapulmonary complication of TB, for which treatment duration of 12 months is often advised.14 Several studies in children and adults have, however, shown that a 6-month SCC is adequate as long as the sterilizing agents pyrazinamide and rifampicin are included in the regimen.7,18–20 In our case both episodes of TB were caused by the same M. tuberculosis strain. We speculate that 6 months of therapy was insufficient for an immune compromised patient. Dormancy of tubercle bacilli despite anti-tuberculosis treatment has been suggested in a mouse model, and DNA could be found in spleen and lung tissue.21,22 It was suggested that the great majority of bacilli were sufficiently damaged by treatment to be incapable of reproduction on culture or on reinoculation into fresh mice.22 Whether this situation applies to man, and what effect a lowered host immunity will have, is uncertain. Our findings suggest, however, that treatment for at least 9 months should be considered in HIV-infected children with TB.4 An alternative approach to prolonged therapy could be the use of isoniazid prophylaxis for life after SCC,1,23,24 but this has not gained general acceptance.25,26 Failure of post-treatment isoniazid prophylaxis has been reported in an adult.27 Problems that can be foreseen with such a regimen in developing countries are non-compliance, the danger of treating relapsed or new disease with monotherapy, and subsequent development of drug-resistant TB. Confirmation of tuberculosis is difficult in children, and in HIV infection even more so, because of frequent development of other illnesses that may mimic an initial presentation of M. tuberculosis.28 Once tuberculosis has been diagnosed and successfully treated, a second episode of TB is seldom considered. We suggest that the taking of samples for repeated culture in HIV-infected children with TB is essential. These cultures should routinely be done during treatment and at follow-up. A second episode of pulmonary TB should always be considered in HIV-infected children.

References 01 Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Guidelines on the management of tuberculosis and HIV infection in the United Kingdom. BMJ 1992; 304: 1231–1233. 02 Telzak EE. Tuberculosis and human immunodeficiency virus infection. Med Clin North Am 1997; 81: 345–360. 03 Espinal MA, Reingold AL, Pérez G et al. Human immunodeficiency virus infection in children with tuberculosis in Santa Domingo, Dominican Republic: prevalence, clinical findings, and response to antituberculosis treatment. J Acquir Immune Deficiency Syndr Human Retrovirol 1996; 13: 155–159.

Case Reports 04 Schaaf HS, Geldenhuys A, Gie RP, Cotton MF. Culture-positive tuberculosis in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 1998; 17: 599–604. 05 Jeena PM, Mitha T, Bamber S, Werley A, Coutsoudis A, Coovadia HM. Effects of the human immunodeficiency virus on tuberculosis in children. Tuberc Lung Dis 1996; 77: 437–443. 06 Centers for Disease Control and Prevention. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994; 43(RR-12): 1–10. 07 Donald PR, Schoeman JF, van Zyl LE, de Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 1998; 2: 704–711. 08 Warren R, Richardson M, Sampson S et al. Genotyping of Mycobacterium tuberculosis with additional markers enhances accuracy in epidemiological studies. J Clin Microbiol 1996; 34: 2219–2224. 09 Van Embden JDA, Cave MD, Crawford JT et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: Recommendations for a standardized methodology. J Clin Microbiol 1993; 31: 406–409. 10 Seifart HI, Gent WL, Parkin DP, van Jaarsveld PP, Donald PR. High-performance liquid chromatography determination of isoniazid, acetylisoniazid and hydrazine in biological fluids. J Chromatogr B 1995; 674: 269–275. 11 Small PM, Shafer RW, Hopewell PC, Singh SP, Murphy MJ, Desmond E, Sierra MF. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Eng J Med 1993; 328: 1137–1144. 12 Taylor B, Smith PJ. Does AIDS impair the absorption of antituberculosis agents? Int J Tuberc Lung Dis 1998; 2: 670–675. 13 Sahai J, Gallicano K, Swick L et al. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Ann Intern Med 1997; 127: 289–293. 14 American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 1994; 149: 1359–1374. 15 Malkin JE, Prazuck T, Simmonet et al. Tuberculosis and human immunodeficiency virus infection in West Burkina Faso: clinical presentation and clinical evolution. Int J Tuberc Lung Dis 1997; 1: 68–74.

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16 Van den Broek J, Mfinanga S, Moshiro C, O’ Brien R, Mugomela A, Lefi M. Impact of human immunodeficiency virus on the outcome of treatment and survival of tuberculosis patients in Mwanza, Tanzania. Int J Tuberc Lung Dis. 1998; 2: 547–552. 17 Pulido F, Pena J-M, Rubio R, Moreno S, González J, Guijarro C, Costa J-R, Vásquez J-J. Relapse of tuberculosis after treatment in human immunodeficiency virus-infected patients. Arch Intern Med 1997; 157: 227–232. 18 Jacobs RF, Sunakorn P, Chotpita Yasunonah T, Pope S, Kelleher K. Intensive short course chemotherapy for tuberculosis meningitis. Pediatr Infect Dis J 1992; 11: 194–198. 19 Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9: 794–801. 20 Alarón F, Escalante L, Pérez Y, Banda H, Chacón G, Dueñas G. Tuberculosis meningitis: short course of chemotherapy. Arch Neurol 1990; 47: 1313–1317. 21 Gangadharam PRJ. Mycobacterial dormancy (editorial). Tuberc Lung Dis 1995; 76: 477–479. 22 De Wit D, Wootton M, Dhillon J, Mitchison DA. The bacterial DNA content of mouse organs in the Cornell model of dormant tuberculosis. Tuberc Lung Dis 1995; 76: 555–562. 23 Iseman MD. Is standard chemotherapy adequate in tuberculosis patients infected with HIV? Am Rev Respir Dis 1987; 136: 1326. 24 Pinching AJ. The acquired immune deficiency syndrome with special reference to tuberculosis. Tubercle 1987; 68: 65–69. 25 Lee T, Masobe P, Schneider H. Proposals for the feasible management of tuberculosis in HIV-seropositive South Africans. South Afr J Med 1995; 85: 68–71. 26 Chintu C, Zumla A. Childhood tuberculosis and infection with the human immunodeficiency virus. J R Coll Physicians Lond 1995; 29: 92–95. 27 Shafer RW, Jones WD. Relapse of tuberculosis in a patient with the acquired immunodeficiency syndrome despite 12 months of antituberculous therapy and continuation of isoniazid. Tubercle 1991; 72: 149–151. 28 Khouri YF, Mastrucci MT, Hutto C, Mitchell CD, Scott GB. Mycobacterium tuberculosis in children with human immunodeficiency virus type 1 infection. Pediatr Infect Dis J 1992; 11: 950–955.

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A Case of Costochondral Abscess due to Corynebacterium minutissimum in an HIV-infected Patient A. Bandera*1, A. Gori1, M. C. Rossi1, A. Degli Esposti1, G. Ferrario1, G. Marchetti1, L. Tocalli2 and F. Franzetti1 1

Institute of Infectious Diseases and Tropical Medicine, “Luigi Sacco” Hospital, University of Milan, Milan, Italy, 2 Department of Microbiology, “Luigi Sacco” Hospital, University of Milan, Milan, Italy

Corynebacterium minutissimum, known as the causative agent of erythrasma, has recently been reported as a clinically significant pathogen in the immunocompromised host. We report for the first time the possible involvement of a multidrug-resistant C. minutissimum strain in a costochondral abscess occurring in an HIV-infected patient. © 2000 The British Infection Society

* Please address all correspondence to: Alessandra Bandera. Clinic of Infectious Diseases, “Luigi Sacco” Hospital, University of Milan, Via G.B. Grassi 74, 4 20157 Milan, Italy. Accepted for publication 7 April 2000.

Introduction Corynebacterium minutissimum is an aerobic, non-sporing, Gram-positive rod, whose habitat is the human skin. Corynebacterium minutissimum is associated with erythrasma, a © 2000 The British Infection Society