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The clinical difficulties faced by Katumba-Lunyenya et al when presented with a sick preterm infant at risk of perinatal transmission of HIV, who later had proven congenital tuberculosis and possible aspergillosis, are enormously challenging, even before considering the infection control, public health, public relations, and media issues that this case highlights.
PREVENTING TRANSMISSION OF HIV
The high maternal viral load, vaginal delivery, and premature birth are all likely to have increased the risk of perinatal transmission of HIV in this case. We do not know the mother’s CD4 count or the circumstances of her delayed antenatal HIV test result. However, it seems possible that her CD4 count was low, and antiretroviral therapy may have been indicated earlier than 24 weeks on maternal health grounds if this information had been available to her doctors. The most important factor in relation to HIV transmission is probably maternal viral load, and this may be reduced by log numbers even if the antiretroviral therapy is only on board for a matter of days. Initiation of maternal antiretroviral therapy earlier in the second trimester might have driven immune reconstitution in the mother and a reduced risk of antenatal transmission of HIV (and possibly tuberculosis). HIV transmission risk would have been further reduced by caesarean section (if acceptable on obstetric grounds) and administration of intravenous zidovudine to the mother during the labour and delivery. The perinatal maternal drug loads the infant with zidovudine before the peak of exposure to HIV during delivery. Prophylaxis of the infant against HIV after birth is difficult in the sick preterm infant because of the availability of only one parenteral antiretroviral agent (zidovudine). There are no definitive studies of preventive strategies in extreme prematurity or optimal drug combinations, and all cases should be discussed with a specialist in paediatric HIV with regard to best current practice. Intravenous zidovudine should be administered to the sick preterm infant as soon as possible after birth. Single agent prophylaxis for HIV transmission is used routinely in low risk cases, but triple prophylactic therapy should be considered for infants who are considered to be at high risk of transmission of the virus, as in this case. Where the neonatologist considers enteral drugs acceptable, oral nevirapine and lamivudine should be added to the intravenous therapy with zidovudine. Such combinations have been used successfully at 27–28 weeks gestation in the United Kingdom in recent years (G Tudor-Williams and H Lyall, personal communication). The intravenous preparation of zidovudine may be replaced by oral zidovudine when the neonate is able to tolerate enteral feeds, and treatment continued for four to six weeks. Monitoring of full blood count for anaemia and neutropenia is advised, and postnatal follow up of the infant to detect infection with HIV should be undertaken as for the term infant.
The case history strongly suggests that the infant was principally infected with Mycobacterium tuberculosis by aspiration of contaminated maternal secretions such as amniotic fluid (as happens when a caseous placental lesion ruptures) rather than through the placenta. It seems unlikely that this infant’s tuberculosis could have been managed differently once recognised, and the demise was so rapid that the antituberculous therapy probably made little difference. This infant needed to receive antituberculous therapy much earlier, perhaps immediately after birth in order to have had a chance against this rare and overwhelming infection. But there was no suspicion of congenital tuberculosis at that stage. It is not clear when the mother was started on blind antituberculous therapy, but this information may have been helpful in planning neonatal management. Infections that compromise placental integrity may increase the risk of transmission of HIV. Clearly co-infection with opportunistic infections (notably sexually transmitted infections, toxoplasma, tuberculosis, cytomegalovirus, etc) must always be considered when an infant is born to an HIV infected mother. When congenital tuberculosis is suspected, a full clinical evaluation including lumbar puncture is required (if practical) and four drug therapy (typically isoniazid, rifampicin, pyrazinamide, and an aminoglycoside) initiated immediately, with addition of steroids if tuberculosis meningitis is present. Alternative drug regimens may be necessary in an infant who cannot tolerate oral agents and should be discussed with a specialist in paediatric infectious disease. Susceptibility testing of the organism once isolated and knowledge of drug resistance in the region where the mother is likely to have acquired the infection should be sought to guide treatment.
It seems likely that this infant had aspergillosis, as the organism was isolated from a skin lesion. It is not clear whether there were specific environmental risk factors in the neonatal unit (building work) or neutropenia in the infant. It seems very reasonable that the infant should receive empiric antifungal therapy, even without this isolate, in view of the deteriorating clinical situation in the context of apparent late onset sepsis and appropriate antibiotic therapy.
The authors have described a tragic case which highlights the need for improvements in delivery of routine antenatal screening to high risk populations and challenges us all to actively consider opportunistic infections when faced with a sick preterm infant in the context of a severely immunosuppressed mother with HIV. Central to delivering optimal prophylaxis of HIV and management of rare congenital infections is good communication between the HIV physician, the obstetrician, the neonatal team, and a specialist in paediatric infectious diseases.
I am grateful to H Lyall and G Tudor-Williams for helpful discussions.