Vd 33 (Suppl), No. 1,1993 Rimd in U.S.A. Intravenous Immune Globulin for the Prevention of Infections in Children with Symptomatic Human Immunodeficiency Virus Infection1 LYNNE M. MOFENSON AND JOHN MOYE, JR. Pediatric, Adolescent and Maternal AIDS Branch. National Institute of Child Health and Human Developmenr, National Institutes of Health, Bethesda. Maryland 20852 ABSTRACT. Infection with human immunodefw vi- moral arm of the immune system (1). Such Well abnormalities rus (HIV) caw a progressive immunodeficiency, often appear to be multifactorial in origin, with demonstration of both manifested in adults by the development of infections with intrinsic B-cell defects and defects secondary to CD4+ helper relatively me, opportunistic organisms. However, in HIV- dysfunction (1-4). Functional abnormalities of B lymphocytes infected children, recurrent serious infections with common noted in vitro include elevated spontaneous proliferation, in- encapsulated bacteria, as well as recurrent minor bacterial creased numbers of spontaneous plaque-forming cells in the and viral infections, ltmy be early and frequent ntanifesta- peripheral blood, enhanced responsiveness to B-cell growth fac- tions of HIV disease. The use of i.v. immune globulin tors, and refractoriness to normal in vitro signals for B-cell (MG) has been shown to prevent infections in patients activation (1). In vivo manifestations of dysfunction include with primary immnnodefm and in uncontrolled &dies hypergammaglobulinemia, circulating immune complexes, an of HIV-infected children. This article reviews the problem inability to mount an appropriate serologic response after im- of and immunologic predisposition for reemrent infections munization, and an increased frequency of common bacterial in pediatric HIV infection and reports on the use of MG and viral infections. for prophylaxis. Updated analysis fnw the National Insti- Although B- and T-cell dysfunction are seen in both HIV- tute of Child Health pad H~mrnDevelopment MGClin- infected adults and children, the consequences of B-cell dysfunc- ial Trial, a multkente!r, doubbblind, placebcxontrolled tion may be more pronounced in children, particularly those trhl of the safety and efficacy of MGfor the prevention with vertically acqWinfection. In adults, even if response to of infections in children with symptomatic HIV infection, new antigens is diminished, preexisting memory cells provide is presented. Between March 1988 and January 1991,376 some immunity fiom infection with common pathogens. How- children with clinical or immuw1ogic evidence of HIV ever, if defective B-cell function occurs early in life, before the disease who were randomized to receive MGor albmnin development of specific memory cells, recurrent and severe placebo were enrolled in this trial. In children with an entry infection with otherwise common organisms may result. CD4+ count of 200/mm3or higher, MG signifiitly In children with HIV infection, recurrent infection with cod mmeased the time ftee from serious bacterial infections mon bacterial and viral organisms is a frequent and early mani- and significantly decreased the rates of minor bacterial festation of HIV disease. The similarity of the type of infections infections and viral infections. (Pcdiatr Res 33 (Suppl): seen in HIV-infected children to those seen in children with SSO-SSS, 1993) congenital hypogammaglobulinemiaprovided the early rationale for use of IVIG for infection prophylaxis in pediatric HIV Abbreviations infection. This article briefly reviews the problem of and the immunologic pxdkposition for recurrent infections in HIV HIV, human immunodefichcy virus infected children and summarizes the published reports on the MG, intravenous immune globulin use of MG for infection prophylaxis, including updated and NICHD, National Institute of Child Health & Human newly analyzed data from the NICHD IVIG Clinical Trial. Development Although the focus of this article is on the use of IVIG for PCP, Pnwmcytis carinii pneumonia preexposure prophylaxis of infections, other current and poten- ZDV,zidovdh tial uses for MGin pediatric HIV infection include treatment CDC, Centers for Disease Control of HIVassociated thromboqtopenia, treatment of cytomeg- ACE, AIDSClinicll Trial Gmop alovirus and Parvovirus B19 infection, and the potential use of hyperimmune HIV immune globulin for treatment of HIV in fection and prevention of vertical tnmmkion (5,6). Infection with HN is characterized by a progressive immu- RECURRENT INFECTIONS IN HIV-INFECTED CHILDREN nologic deficiency manifested by depletion of CD4+ helper HIV infection in adults is associated with the development of lymphocytes, resulting in opportunistic infections and a severe infections with relatively rare, opportunistic organisms. In con- deficit in cellular immunity. Additionally, alterations in B-lym- trast, the development of recurrent serious systemic illness caused phocyte function are common, resulting in deficits in the hu- by common encapsulated bacteria is so common in HIV-infected Comspondence:Lynne M. Mofenson, M.D., Amchte Branch Chieffor Clinical children that the federal CDC modified the pediatric AIDS case R-h, wk Addesrmt & Matcroal AIDS Branch, National Institute of definition in 1987 to include recurrent serious bacterial infections Child Health & Human Development, National Mtutm of Health, 6100 Execu- (7). tive Blvd., Room 4B1 I, Rockvilk, MD 20852. as an AIDSindicator disease Although PCP is the most 'Portions of this article were modi6ed from Mofenson LM, Sheonr WT 1992 frequent AIDS-defining illness in children, recurrent serious Use of lVlG in &tric HIV infection. Semh Pediatr I* Dis 31-10. bacterial infections occurred in almost 25% of children with P P s1 INFANT CHILDREN ADOLESCEN cLY6 1-1-13 YR ++ Yo& Cky ha@Wdinia, Mmlda et al. (15) nated that 79% of LymphoO.nicr - +++ thdr~~pllmonu~proMema~~~~-a4 - ++ +++ uwillgaacff~~oflabo~-~- -- +++ ++ maarh 70% hv& bpital ahmmmm for an acute respl- kWpmamwkkrkmk * ~in#r~raidenScdpatbgsn.lnasmallprospec- tivdytidfor#dIOsltneohoatof27Hnr-hh%~dchildrenand An- -b~ nutrluA.~~~~trota,HIvin&etsb*badsienif- m did uaiaBbcted C0nb.d pasienb (16). NA Rccrnnntminor~~~rratiE%ercrdirrasEkorylrdw dw,aomrnoninHIV-idu%cdtW&~b-&tlrermaPhert l~rr~oftrr- 4 ++ ++ the numbg alfawm- with ++ ?, .* -. - - --- S82 IbmFEWDN AND MOW3 tive loss of T-bdper mpome to d an* stimuhq thwcfim petients (3 1-39). With the exception of one small comparative appears to be asdatul tlrrith an incns&6 ridr of batted study oomducteci in an older hemophiliac population (39), which infewharaas morc pqrsgive T-bclpsr dysttnction ap= did nat show a benefit of MG on infection prevention, thc pcrrsk>omwhterintbaoowseobHnr~mdtobe studieb~av&tyofb~dbwithMGtherapy,incl~d- aasodatad with a dadine in CI% all number lurd the ouau- ing declslcasGd infictioas and ~tioos,improvements in rmctof gnowtbund wavi#l, a dedist in p24 an* and improvements rresslieasintdevetcd inpedirtricHWiafaeSion,~~QWS~(bybdatedeh~~mdim~vcmcntrrm~ adult~~~can~bepatcnthnyasplriwd. dflnczioa,~nsponse,aedCD4+cdl~0unt. wa- ofrsMlPtjadQn,~tbs~8geHowewff,in~onofthese~Was~d~to ~co4.+aountnoanrrinyosurl~thcePrtyBcdltheuncQatrOUcdaakuedmostoftheshdies,the~uatc abmrmaW8 and dydmXbd 6 ~cizeinthcstudies,thewidelyvaryingregim~ofMG servtxi in infdihts, tbe-m the Ld; of- patient evaluation fw-up, antigen nsponac in immundaeicrlfy dveHIV- hfhta and the use of same jmduct produced befi 1985 that poten- tially collhbd antibody to HIV. Therefore, the National Insti- IVIGPRO&OP~NSIN tuas of~ealthsponsond two ~~lldomizal,controlled, c in dad I3iV-m-W pmphyiaxisinHIV-~~Onestudy(thcMCHDclinical~toexaminethe&cacyofMGfor~on he Won& for pmp&ykisin m-infwchitdren MG Qinical T*) has completad (40) and the other isbeseduponthec~~tyafthetyptand~uencyof(ACIYi051)~n~o~. infixtionsinHIV-~~tothosesanincMdrcnwitb ~0Wtalhumd hskodoficickicd and the suaxdld ust MCHD MG CLINICAL TRIAL of IVIG to pnnnt infixtiom in thedt congenital disoders (30). In the latw half of the 19808, aevcaal invedpton published MethodF. The NICHD MG trial was a multicenter, double- reports indicating the potential benetit of MGfor the prmntion blind, ~bacontrolldstudy to determine whether MG, in a of infections in HIV-hfected children. As summarized in Table dose of 400 mgFg every 28 d, would reduce the risk of serious 1, then have been six pubWbd case reports, invdw 61 tqackkl infttdion or death in HIV-intkded children. Figun 2 patien4 and three co-k:' repor$, involving 5 i treated povidcs an overview of the protocol design. Nonhemophiliac, Table 1. Summary of studies of ZYIG prophylax@ in HZV-in@& childrm' No. of Typt of Authot (-1 prtiehtr . npOrt Mpdose~ Rme Silvcman el d. (31) -.33 - Case $wk &n; 300 LDHt dccbc w/bemy2* Gupta ef d. (32)' ' 7 Case 1-wk edc&W, 200 supprslor cell function w%svar~2* imwt Wood el d. (33) 1 Case 4oomdLgloading; No btdalidkctiom ~m%ksemy over 19- mo schaaa et al. (34) Imo eadation; 400 rcasfebrileepisodes mgFBmm0 and Moar; LDH Ww, normalized gt0Wth-d- licwmlmt; no- deaths Williams ef al. (35) 2-wk escalation; 200 Less savae infcctiow mgFgenry3-4 ndPced- wk tionIcqgth;* i@ Case Lessirlfktb~lessbog pitlrlmc- *,&mmes in p24 rmtigcn 14 treated ~mg/lysvary2~ Dcasrrakinsspsisand spicodes; 27 untreated P t&de in- arokiacD4+ 00unt;bsaaein wGm#-X #r bcremd .4 les@mc&LL3ii& ctine loomdksevery=Jk E~survival IVIG PROPHYLAXIS IN HIV-INFECTED CHILDREN S83 NlCHD lVlG Clinical Trial A os/owm - Mrn DLSKIH Phue Ill, Multkonter. Pheobo- cocltroN.4 D0UM.-Blind 6My POPULATION 176 HlV-in- &IWO#I