D E C E M B E R 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 70 Immune reconstitution inflammatory syndrome (IRIS) refers to an ‘unexpected’ and paradoxical clinical deterioration in the period immediately after initiation of antiretroviral therapy (ART). Diagnosis of IRIS relates to the time frame after initiation of antiretroviral therapy ART, response to ART and exclusion of alternative diagnoses. Boulware et al. proposed criteria for children.1 There are fewer data on incidence, prevalence and clinical descriptions in infants and children than in adults. Studies report a prevalence of up to 21% in South African infants.2 IRIS is commonly associated with mycobacterial infections, mainly bacille Calmette-Guérin (BCG), Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM).2-5 Other condi- tions such as skin disease, herpes simplex, cryptococcal meningitis and immune diseases such as Guillain-Barré syndrome are also reported.1,3 Age and geographical lo- cation are important determinants of the risk for each disease. Table I summarises the most pertinent paediatric literature. M. TUBERCULOSIS IRIS EPIDEMIOLOGICAL CONSIDERATIONS IN HIV- INFECTED CHILDREN Tuberculosis (TB) is a common opportunistic infection in HIV-infected African children. Rates of 53.3 cases/100 pa- tient-years are reported in children not on highly active antiretroviral therapy (HAART).6 High rates of exposure to potentially infectious source cases are well documented in HIV-exposed infants7 and rates of disease of 1 596 cases per 100 000 HIV-infected infants are documented in Cape Town.8 Young age and HIV-related immunosup- pression contribute to this high disease burden. Recurrent episodes of TB are well documented and are caused by both relapse and re-infection.9 In a cohort studied before and after widespread availability of ART, 30% of children with HIV and culture-confirmed TB had received prior TB therapy.6 Rates of drug-resistant TB vary between settings. Drug resistance was reported in 17% of HIV-infected children with TB, 6.8% having resistance to both rifampicin and isoniazid.10 Children with prior TB therapy are at higher risk of resistance.11 There may be an incomplete thera- peutic response to 6 months of standard anti-TB ther- apy.9 Up to a third of children initiating HAART may be on anti-TB therapy.6,12 Cohort data from low-resource set- tings indicate that the majority of children still initiate HAART at very low CD4 counts and with significant clini- cal disease.13 These children are at high risk for IRIS and incident TB from new exposure to M. tuberculosis. With improved access to HAART, an up to 70% reduction in the incident TB can be achieved.6,14 DIAGNOSTIC CONSIDERATIONS The diagnosis of TB in HIV-infected children remains dif- ficult. Signs and symptoms overlap with advanced HIV. Clinical scoring tools have poor specificity in HIV-infect- ed children.15,16 Sputum is difficult to collect in young children, and gas- tric washings are frequently not performed.17 Culture yields from gastric washings and induced sputa are low in children. Although yields of up to 40%18 have been re- ported in research settings, the yield in clinical settings is IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN CHILDREN C L I N I C A L Helena Rabie1, FCP (Paed) Tammy Meyers2, FCP (Paed) Mark F Cotton1, PhD 1Department of Paediatrics and Child Health, Tygerberg Children’s Hospital and Stellenbosch University, Tygerberg, W Cape 2Harriet Shezi Paediatric ARV Clinic, Chris Hani Baragwanath Hospital, Johannesburg Paradoxical deterioration due to immune reconstitution inflammatory syndrome (IRIS) occurs in up to 21% of children initiating antiretroviral therapy. Mycobacterial diseases are the most common, with BCG-vaccine adenitis predominating in infants and Mycobacterium tuberculosis (TB) in older children. The difficulty of diagnosing TB in HIV-infected children and the increasing risk of drug-resistant TB complicate the diagnosis and management of both paradoxical IRIS and post-antiretroviral therapy TB. History and clinical assessment remain key strategies in the management of these infants and children. There are no prospective studies investigating diagnostic criteria and therapeutic strategies in children. T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E D E C E M B E R 2 0 0 9 71 lower.19 In children with a high index of suspicion for TB, microbiological confirmation can be obtained in 55%, increasing to 80% with significant pulmonary infiltra- tion.16 Chest radiographs are difficult to interpret owing to ubiquitous chronic underlying HIV-associated lung disease. Tuberculin skin tests have a reduced sensitiv- ity despite adjusting the extent of induration from 10 mm to 5 mm.20 The value of interferon-gamma release assays in HIV-infected children is still under study. Nega- tive results do not exclude TB,21 and tests are expensive. Although failure of therapy for an opportunistic infec- tion is considered an exclusion criterion for IRIS, IRIS has been diagnosed in adults with inadequately treated drug-resistant TB.22 As the diagnosis of TB is seldom con- firmed by culture and drug sensitivity is often not avail- able, it may be difficult to differentiate IRIS from poor response to treatment and drug resistance. It may not be possible to confirm a response to HAART because of lack of access to virological testing. If events occur soon after initiation of therapy, significant reductions in viral load and clinical responses may not yet have occurred. THERAPEUTIC CONSIDERATIONS Current dosages of anti-TB medicines, especially isoni- azid and rifampicin, are insufficient in all children; this is probably exacerbated in children with HIV, in whom malabsorption is common.23-25 Rifampicin reduces exposure to protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), thereby compromising HAART efficacy. Riton- avir-based HAART, previously recommended for co- treated children on PIs, has been associated with poorer virological outcomes.26 POST-HAART TB AND UNMASKING IRIS Besides the general principles proposed by Boulware,1 there are no proposed criteria to distinguish true IRIS from incident TB or missed disease prior to HAART initiation. Adult clinicians have suggested that all cases of TB after initiation of HAART should be termed post-HAART TB, with only cases occurring in the first 3 months accompanied by heightened clinical features classified as IRIS.27 Data from cohort studies report TB rates of 3.4 - 6.2% in African children after initiating HAART6,28 (Table I). In infants TB-IRIS is thought to be less common than BCG-IRIS.2 Clustering of these cases in the first 100 days after HAART initiation is reported from cohort studies. In a large Ugandan study, a 2.7- fold increase in risk for TB was observed early after the initiation of HAART.28 This could be due to inadequate screening procedures, as the converse was noted in a study where active screening was done.6 Few studies provide detailed assessment of the severity of disease, an essential component in distinguishing between IRIS, incident TB and disease missed prior to initiating HAART. Zampoli et al. described 7 children with post-HAART pulmonary TB IRIS, and 1 with additional extrapulmonary disease.29 Three (43%) had received therapy prior to the initiation of HAART. Culture was positive in 4 of the 7 cases. Of these, 1 had multidrug resistance, having stopped anti-TB therapy 3 weeks before initiating HAART. All chest radiographs showed significant adenopathy with airways compression, extensive parenchymal infiltration and pleural reactions.29 Although all IRIS is associated with significant inflammatory response, radiological findings are similar in HIV-infected children not on HAART.10 Clinicians therefore need to judge the relative severity of these conditions. Exposure to M. tuberculosis shortly after initiation of HAART could conceivably present as post- HAART TB IRIS.30 This is especially relevant in children immunologically primed by receiving BCG at birth. IRIS caused by both BCG and TB in the same patient is now well documented in two prospective paediatric co- horts. In the NEVEREST study 50% of children with TB also had BCG IRIS.2 In the CHER cohort, 19% of children with BCG IRIS adenitis also had TB IRIS.31 PARADOXICAL IRIS Delaying the initiation of ART in TB cases with severe im- munodeficiency is associated with increased HIV-related mortality.32 Currently the World Health Organization (WHO) recommends that children with severe immune suppression or stage 4 disease should initiate ART 2 - 8 weeks after the initiation of anti-TB therapy.33 The basic diagnostic criteria for IRIS1 should be met first when diagnosing paradoxical IRIS. The proposed case definitions for TB paradoxical IRIS, although appropriate for well-resourced settings, are problematic in lower-re- source settings. This is due to the diagnostic uncertainty of TB in HIV-infected children and difficulty in excluding alternative diagnoses and confirming a response to ART because of inability to measure CD4 counts or viral load, especially in rural areas. Few data exist on the risk of paradoxical IRIS. The study from Uganda reports only 2 cases of paradoxical IRIS.27 Zampoli et al. recently described the clinical events in 4 children receiving anti-TB therapy for 21 - 59 days be- fore initiation of ART, who subsequently developed TB IRIS between 6 and 105 days later. Skin test conversion was documented in 1 child and was positive at the time of exacerbation in another. Two children presented with deterioration of pulmonary TB, 1 developed local adeni- tis and another abdominal adenitis. One child died.29 There is little information on clinical features and man- agement of neurological paradoxical IRIS in children. In adults these account for 12% of cases of paradoxi- cal TB IRIS.34 Similarly, intra-abdominal TB IRIS is com- D E C E M B E R 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 72 mon in adults, occur- ring in 37% of cases.35 Although paediatric cases do occur (Helena Rabie – unpublished data), little is known about the prevalence in children. It is challenging to ex- clude drug-resistant TB and failure of TB ther- apy for other reasons in these children. Re- sistance was common in an adult series from Cape Town.22 The case in Fig. 1 illustrates the diagnostic difficulties in a setting of paradox- ical IRIS and resistance to TB therapy. GENERAL EVALUATION Contact with a source case has been docu- mented in 30 - 54% of HIV-infected chil- dren with TB.6,10 TB can therefore be prevented and detected through a careful history look- ing for a source case in the household and extended social circle. In older children and adolescents transmis- sion may occur outside the family due to social mobility, and it is likely that a history of con- tact will be a less sen- sitive marker to distin- guish incident TB from IRIS. Reviewing adherence to anti-TB therapy and ART is essential to eval- uate children with sus- pected paradoxical TB IRIS. Documentation of suspected contact with a source patient who may have drug-resist- ant TB is also crucial. In W al te rs e t al .6 A ll TB Sm it h et a l.2 A ll IR IS Pu th an ac it e t al .3 A ll IR IS N ut ta ll et a l.4 6 BC G o nl y Za m po li et a l.2 9 TB o nl y an d as pe ct s of B CG A ge (a ll) 8 m on th s 7. 9 ye ar s 8 - 12 1 m on th s 23 .5 m on th s Ep is od es /c hi ld re n (% ) 34 e pi so de s /1 69 c hi ld re n (2 1% ) 32 e pi so de s/ 15 3 ch ild re n (1 9% ) 21 e pi so de s /3 31 c hi ld re n (6 .3 % ) 11 c as es 10 u nm as ki ng T B , 4 pa ra do xi ca l A ge , c as es v . c on tr ol s (p -v al ue ) 7 m on th s v. 1 0 m on th s (0 .0 07 ) 8. 2 ye ar s v. 7 .8 y ea rs (0 .5 0) 5 m on th s v. 2 7 m on th s (< 0. 00 1) C D 4% , c as es v . c on tr ol s (p -v al ue ) 3. 1 v. 5 .5 (0 .0 2) 12 .3 % v . 1 2. 0% (0 .5 5) 10 .3 % (c as es o nl y) A bs ol ut e C D 4 co un t, ca se s v. co nt ro ls (p -v al ue ) 74 1 v. 1 0 75 (0 .0 14 8) Lo g ba se lin e H IV R N A c op ie s/ m l, ca se s v. c on tr ol s (p -v al ue ) 5. 37 v . 5 .3 7 H IV R N A c op ie s/ m l ( 0. 96 ) 6. 1 v. 5 .6 (0 .0 01 ) Vi ra l l oa d > 75 0 00 0 (% ) 79 % v . 5 5% (0 .0 44 ) Ti m e to e ve nt (m ea n (r an ge )) 16 d ay s (7 - 1 15 ) 6 w ee ks (2 - 2 1) 34 d ay s (1 5 - 60 ) B C G 24 /3 4 2/ 32 21 /2 1 TB 6/ 34 3/ 32 11 /1 1, 4 p ar ad ox ic al IR IS 14 /1 4 TB a nd B C G 6/ 34 M A C 4/ 32 N TM 5/ 32 H er pe s zo st er 7/ 32 H er pe s la bi al is 1/ 34 6/ 32 H er pe s en ce ph al it is 1/ 32 C ry pt oc oc ca l m en in gi ti s 3/ 32 C yt om eg al ov ir us 1/ 34 PC P 1/ 34 Se bo rr ho ei c de rm at it is 1 B ac te ri al s ep si s 2 G B S 1/ 32 B C G = B ac ill e C al m et te -G ué ri n; T B = t ub er cu lo si s; M A C = M . a vi um -i nt ra ce llu la re ; N TM = n on -t ub er cu lo us m yc ob ac te ri a; P C P = P ne um oc ys ti s pn eu m on ia ; G B S = g ro up B s tr ep to co cc al d is ea se . TA BL E I. CO M PA RI SO N O F ST U D IE S IL LU ST RA TI N G A SP EC TS O F PA ED IA TR IC IR IS T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E D E C E M B E R 2 0 0 9 73 adults diagnosed with paradoxical TB IRIS, resistance is a major clinical confounder.22 Weight gain on therapy may be an important and measurable clinical marker supporting IRIS rather than clinical deterioration. This information, together with clustering in the first 100 days, may allow for a possible differentiation between incident TB and IRIS in younger children. Culture for M. tuberculosis and drug sensitivity testing should be con- ducted whenever possible. Clinical judgement should guide clinicians as to additional investigations needed to exclude additional diagnoses such as acute bacterial infections, drug reactions and other opportunistic infec- tions or malignancies. MANAGEMENT Children are at higher risk than adults of death and hospitalisation in the period immediately after HAART initiation. Mortality of 17.4/100 000 patient-years in the first 3 months of therapy has been reported. Up to 30% require hospitalisation in the first 6 months on thera- py. Two-thirds of the admissions are related to bacte- rial infection and pneumonia.36,37 Withholding antibiotic therapy and other interventions at initial presentation is therefore very dangerous when TB IRIS is suspected. As in adults, therapy for TB IRIS includes the anti-TB therapy and continuation of HAART. However, if the IRIS event is life-threatening or likely to cause permanent disability (i.e. TB meningitis with clinical deterioration), HAART may be discontinued temporarily. Children on PIs can stop all drugs simultaneously. There is a signifi- cant risk for resistance when stopping efavirenz or ne- virapine.38 Clinicians need to weigh the risk of inducing NNRTI resistance against that of continuing either NRTIs or boosted lopinavir/ritonavir for 7 - 14 days. The safety of these strategies is unknown in this scenario. Steroids improve outcomes for adults with moderate to severe TB IRIS, but there are no randomised studies in children.39 As in adults, clinicians must weigh the risk of resistant TB prior to starting steroid therapy. Other modalities used (but not studied) include non-steroi- dal anti-inflammatory drugs (NSAIDs), thalidomide and leucotriene receptor antagonists.40-44 Despite the lack of data, it is reasonable to stratify the use of supportive therapy as follows: NSAIDs for mild to moderate disease, and steroids for severe disease. In cases where there is a prior indication, i.e. meningitis, steroids should always be used. It is unclear whether pre-emptive steroids or NSAIDs can prevent IRIS (a trial in adults is underway). BCG-RELATED IRIS BCG is the most common mycobacterial IRIS in infants given BCG at birth.2 Vaccine site ulceration and abscess formation, ipsilateral adenitis and exacerbation of dis- seminated disease occur.45 Where ART is delayed until clinically indicated, 6% of all children and 14% of in- fants experience BCG-related adverse events. In this set- ting, age at initiation is the most important risk factor.2,46 When children access therapy early and at a younger age, a low CD4 count is the most important predictor.45 Although there is a significant reduction in the risk of IRIS with early initiation of ART adverse events are com- mon in these infants also.31 Fig. 1. Drug-resistant TB presenting as paradoxical IRIS in a 12-year-old girl with pulmonary and abdominal TB and severe immune suppression (chest radiograph a). She was sputum smear positive and had a CD4 count of 31 cells/µl. Anti-TB therapy with four drugs was initiated and she responded well, smear conversion taking place within 3 weeks. ART was started 3 weeks after initiation of TB therapy, and 7 days later she developed a high fever, severe abdominal pain and food intolerance. The sputum smear was now positive, and a chest radiograph (b) suggested miliary TB. Steroids were added with some clinical improvement. Rifampicin resistance was confirmed after 48 days on TB therapy and 27 days on ART. a b D E C E M B E R 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 74 The diagnosis of IRIS remains clinical. Where systemic disease is suspected, extensive investigation may be re- quired. Although no prospective studies have been con- ducted, it is likely that local and regional IRIS requires no specific therapy. However, disseminated disease requires aggressive therapy that should be discussed with an ex- pert. Danish strain BCG is resistant to current standard doses of isoniazid as well as to pyrazinamide and ethion- amide.47 Induction of resistance in inappropriately treat- ed cases with systemic disease has been documented.48 NON-TUBERCULOSIS MYCOBACTERIA One study from Thailand reports on non-tuberculosis mycobacterial IRIS in children. Of 153 children initiating therapy at a median age of 7.9 years, 9 had IRIS caused by non-tuberculosis mycobacteria, 2 with paradoxical deterioration and 7 with unmasking disease. The rate was 5.9 cases per 100.5 There are no data for South Af- rican children, although cases do occur (Helena Rabie - unpublished data). IRIS INVOLVING SKIN CHANGES Skin changes are the most common form of IRIS in adults, but there are fewer data in children. Unpublished data from KwaZulu-Natal reported by Boulware in a review on IRIS indicated that 53% of children had a new on- set of rash after the initiation of HAART.1 These included molluscum contagiosum (8%), tinea capitis (20%), warts (16%), impetigo (12%), herpes zoster (5%), and other fungal rashes (24%).1 Earlier cohorts reported that 11% of children developed herpes zoster. Children at risk were negative for varicella antibody despite a previous history of varicella and had severe immunodeficiency before treatment.49 Exacerbation of warts and molluscum contagiosum is commonly seen. If areas such as the face are involved, this disfigurement can be very disruptive and may lead to non-adherence. OTHER PHENOMENA Cryptococcus neoformans is common in South African adults50 but less common in children. In children <15 years of age, the incidence is 1 per 100 000 population.51 C. neoformans IRIS of both the central nervous system and the lungs occurs occasionally.52 Guillain Barré syndrome, myocardial dilatation, exacer- bation of JC virus progressive multifocal leucoencepha- lopathy, leprosy, Kaposi’s sarcoma, cytomegalovirus, Pneumocystis pneumonia (PCP), opsoclonus-myoclonus syndrome, toxoplasmosis and other entities have been reported in adults and in children.3,41,53-55 CONCLUSION IRIS is common in children. BCG is important in infants and TB is more prevalent in older children. Although the morbidity is thought to be low, IRIS may be diagnostically challenging and carry a high morbidity. A higher drug burden may result in decreased therapeutic success, with possible non-adherence and more potential for drug interactions as well. A careful history and clinical review remain important tools in the diagnosis and management of these conditions. REFERENCES 1. Boulware DR, Callens S, Pahwa S. Pediatric HIV immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS 2008; 3: 461-467. 2. Smith K, Kuhn L, Coovadia A, et al. Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy. AIDS 2009; 23: 1097-1107. 3. Puthanakit T, Oberdorfer P, Akarathum N, Wannarit P, Sirisanthana T, Sirisanthana V. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected Thai children. Pediatr Infect Dis J 2006; 25: 53-58. 4. Puthanakit T, Oberdorfer P, Punjaisee S, Wannarit P, Sirisanthana T, Sirisanthana V. Immune reconstitution syndrome due to bacillus Calmette-Guerin after initiation of antiretroviral therapy in children with HIV infection. Clin Infect Dis 2005; 41: 1049-1052. 5. Puthanakit T, Oberdorfer P, Ukarapol N, et al. Immune reconstitution syndrome from nontuberculous mycobacterial infection after initiation of antiretroviral therapy in children with HIV infection. Pediatr Infect Dis J 2006; 25: 645-648. 6. Walters E, Cotton M, Rabie H, Schaaf H, Walters L, Marais B. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. BMC Pediatr 2008; 8: 1. 7. Cotton MF, Schaaf HS, Lottering G, Weber HL, Coetzee J, Nachman S. Tuberculosis exposure in HIV-exposed infants in a high-prevalence setting. Int J Tuberc Lung Dis 2008; 12: 225-227. 8. Hesseling AC, Cotton MF, Jennings T, et al. High incidence of tuberculosis among HIV-infected infants: evidence from a South African population-based study highlights the need for improved tuberculosis control strategies. Clin Infect Dis 2009; 48: 108-114. 9. Schaaf HS, Krook S, Hollemans DW, Warren RM, Donald PR, Hesseling AC. Recurrent culture-confirmed tuberculosis in human immunodeficiency virus- infected children. Pediatr Infect Dis J 2005; 24: 685-691. 10. Schaaf HS, Marais BJ, Whitelaw A, et al. Culture-confirmed childhood tuberculosis in Cape Town, South Africa: a review of 596 cases. BMC Infect Dis 2007; 7: 140. 11. Schaaf HS, Marais BJ, Hesseling AC, et al. Surveillance of antituberculosis drug resistance among children from the Western Cape Province of South Africa – an upward trend. Am J Public Health 2009; 99: 8: 1486-90 12. Moultrie H, Yotebien M, Kuhn L, Meyers T. Mortality and virological outcomes of 2105 HIV-infected children receiving ART in Soweto, South Africa. Presented at the16th Conference on Retroviruses and Opportunistic Infections, 8 - 11 February 2009, Montréal (Abstract 97). 13. Sutcliffe CG, van Dijk JH, Bolton C, Persaud D, Moss WJ. Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa. Lancet Infect Dis 2008; 8: 477-489. 14. Martinson NA, Moultrie H, van Niekerk R, et al. HAART and risk of tuberculosis in HIV-infected South African children: a multi-site retrospective cohort. Int J Tuberc Lung Dis 2009; 13: 862-867. 15. Hesseling AC, Schaaf HS, Gie RP, Starke JR, Beyers N. A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis. Int J Tuberc Lung Dis 2002; 6: 1038-1045. 16. Marais BJ, Graham SM, Cotton MF, Beyers N. Diagnostic and management challenges for childhood tuberculosis in the era of HIV. J Infect Dis 2007; 196: Suppl 1: S76-85. 17. Eamranond P, Jaramillo E. Tuberculosis in children: reassessing the need for improved diagnosis in global control strategies. Int J Tuberc Lung Dis 2001; 5: 594- 603. 18. Zar HJ, Hanslo D, Apolles P, Swingler G, Hussey G. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005; 365: 130-134. 19. Hatherill M, Hawkridge T, Zar HJ, et al. Induced sputum or gastric lavage for community-based diagnosis of childhood pulmonary tuberculosis? Arch Dis Child 2009; 94: 195-201. 20. Schaaf HS, Geldenduys A, Gie RP, Cotton MF. Culture-positive tuberculosis in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 1998;17: 599-604. 21. Davies MA, Connell T, Johannisen C, et al. Detection of tuberculosis in HIV-infected children using an enzyme-linked immunospot assay. AIDS 2009; 23: 961-969. 22. Meintjes G, Rangaka MX, Maartens G, et al. Novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance. Clin Infect Dis 2009; 48: 667-676. 23. Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child 2005; 90: 614-618. 24. Schaaf HS, Victor TC, Engelke E, et al. Minimal inhibitory concentration of isoniazid in isoniazid-resistant Mycobacterium tuberculosis isolates from children. Eur J Clin Microbiol Infect Dis 2007; 26: 203-205. T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E D E C E M B E R 2 0 0 9 75 25. Schaaf HS, Willemse M, Cilliers K, et al. Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis. BMC Med 2009; 7: 19. 26. Reitz CA, Meyers T, Hu C-C, Strehlau R, Sherman G, Abrams EJ, Kuhn L. Virologic response to protease-inhibitor-based antiretroviral therapy among children less than 2 years of age co-treated for tuberculosis in South Africa. Presented at the 16th Conference on Retroviruses and Opportunistic Infections, 8 - 11 February 2009, Montréal (Abstract 910). 27. Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8: 516-523. 28. Bakeera-Kitaka S, Kekitiinwa A, Dhabangi AE, et al. Tuberculosis immune reconstitution syndrome among Ugandan children. Presented at the Infectious Diseases Society of America Annual Conference, 4 - 7 October 2007, San Diego (Abstract 921). 29. Zampoli M, Kilborn T, Eley B. Tuberculosis during early antiretroviral-induced immune reconstitution in HIV-infected children. Int J Tuberc Lung Dis 2007; 11: 417-423. 30. Innes SHS, Cotton MF. Cavitation of the Ghon focus in an HIV infected infant who acquired tuberculosis after the initiation of HAART. Southern African Journal of HIV Medicine 2009; 10(1): 44-48. 31. Rabie H, Violari A, Madhi S, Gibb DM, Steyn J, Van Niekerk R, et al. Complications of BCG vaccination in HIV infected and uninfected children: evidence from the Children with HIV Early Antiretroviral Therapy (CHER) study. Presented at the 15th Conference on Retroviruses and Opportunistic Infections, 3 - 6 February 2008, Boston (Abstract 600). 32. Karim SA, Naidoo K, Grobler A, et al. Initiating ART during TB treatment significantly increases survival: Results of a randomized controlled clinical trial in TB/HIV-co- infected patients in South Africa. Presented at the 16th Conference on Retroviruses and Opportunistic Infections, 8 - 11 February 2009, Montréal (Abstract 36A). 33. World Health Organization. Antiretroviral therapy of HIV infection in infants and children: towards universal access. 2006 http://www.who.int/hiv/pub/guidelines/ paediatric020907.pdf (accessed 20 November 2009). 34. Pepper DJ, Marais S, Maartens G, et al. Neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series. Clin Infect Dis 2009; 48: e96-107. 35. Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007; 21: 335-341. 36. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA 2007; 298: 1888. 37. Puthanakit T, Aurpibul L, Oberdorfer P, et al. Hospitalization and mortality among HIV-infected children after receiving highly active antiretroviral therapy. Clin Infect Dis 2007; 44: 599-604. 38. Cressey TR, Green H, Khoo S, et al. Plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reverse-transcriptase inhibitors in HIV type 1-infected children. Clin Infect Dis 2008; 46: 1601-1608. 39. Meintjes GWR, Morroni C, Pepper D, et al. Randomized placebo-controlled trial of prednisone for the TB immune reconstitution inflammatory syndrome. Presented at the 16th Conference on Retroviruses and Opportunistic Infections, 8 - 11 February 2009, Montréal (Abstract 34). 40. Kestens L, Seddiki N, Bohjanen PR. Immunopathogenesis of immune reconstitution disease in HIV patients responding to antiretroviral therapy. Curr Opin HIV AIDS 2008; 3: 419-424. 41. Rapose A, Sarvat B, Sarria JC. Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. Cardiology 2008; 110: 142-144. 42. Schoeman JF, Fieggen G, Seller N, Mendelson M, Hartzenberg B. Intractable intracranial tuberculous infection responsive to thalidomide: report of four cases. J Child Neurol 2006; 21: 301-308. 43. Schoeman JF, Springer P, Ravenscroft A, et al. Adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role. J Child Neurol 2000; 15: 497-503. 44. Skiest DJ, Hester LJ, Hardy RD. Cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. J Infect 2005; 51: e289-297. 45. Hesseling AC, Rabie H, Marais BJ, et al. Bacille Calmette-Guerin vaccine-induced disease in HIV-infected and HIV-uninfected children. Clin Infect Dis 2006; 42: 548- 558. 46. Nuttall JJ, Davies MA, Hussey GD, Eley BS. Bacillus Calmette-Guerin (BCG) vaccine- induced complications in children treated with highly active antiretroviral therapy. Int J Infect Dis 2008; 12: e99-105. 47. Ritz N, Tebruegge M, Connell TG, Sievers A, Robins-Browne R, Curtis N. Susceptibility of Mycobacterium bovis BCG vaccine strains to antituberculous antibiotics. Antimicrob Agents Chemother 2009; 53: 316-318. 48. Hesseling AC, Schaaf HS, Hanekom WA, et al. Danish bacille Calmette-Guerin vaccine-induced disease in human immunodeficiency virus-infected children. Clin Infect Dis 2003; 37: 1226-1233. 49. Tangsinmankong N, Kamchaisatian W, Lujan-Zilbermann J, Brown CL, Sleasman JW, Emmanuel PJ. Varicella zoster as a manifestation of immune restoration disease in HIV-infected children. J Allergy Clin Immunol 2004; 113: 742-746. 50. Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009; 51: 130-134. 51. The burden of cryptococcosis in South Africa: Statistical Notes February 2008. http://www.doh.gov.za/docs/stats/2008/cryptococcosis.pdf (accessed 20 November 2009). 52. van Toorn R, Kritzinger F, Rabie H. Acute demyelinating encephalomyelitis (ADEM), cryptococcal reactivation and disseminated herpes simplex in an HIV infected child following HAART. Eur J Paediatr Neurol 2005; 9: 355-359. 53. Kharkar V, Bhor UH, Mahajan S, Khopkar U. Type I lepra reaction presenting as immune reconstitution inflammatory syndrome. Indian J Dermatol Venereol Leprol 2007; 73: 253-256. 54. Nuttall JJ, Wilmshurst JM, Ndondo AP, et al. Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitution inflammatory syndrome. Pediatr Infect Dis J 2004; 23: 683-685. 55. van Toorn R, Rabie H, Warwick JM. Opsoclonus-myoclonus in an HIV-infected child on antiretroviral therapy - possible immune reconstitution inflammatory syndrome. Eur J Paediatr Neurol 2005; 9: 423-426.