In this study, we observed signs and symptoms that were significantly more prevalent at visits that occurred during acute primary HIV infection, compared with noninfection visits in the same cohort. Rash, failure to thrive, lymphadenopathy, hospitalization, hepatomegaly, thrush, dehydration, and pneumonia were more prevalent at visits during acute infection than at other clinic visits. Most signs and symptoms were highly specific but not very sensitive, and they were more likely to occur in older infants than in infants <2 months of age. Maternal HIV RNA load was not predictive of an infant experiencing acute infection syndrome. In addition, acute infection syndrome was not associated with higher peak or set point plasma HIV RNA viral load in the infant or with higher mortality. However, the presence of acute symptoms was associated with significantly higher HIV RNA loads later in infection.
During infection, acute HIV infection and the accompanying host-immune response lead to systemic symptoms, particularly involving lymph nodes, skin, and pharynx [1
]. In infant cohorts, particularly in resource-constrained settings, a variety of infections are common throughout infancy, and discriminating symptoms and signs of acute HIV infection is challenging. Several symptoms, such as fever, that are associated with acute HIV infection in adults were seen commonly in both acutely infected and noninfected infants in our cohort and were not significantly associated with acute infection. In addition, because infants cannot self-report flu-like symptoms—including pharyngeal discomfort, headache, or myalgias—objective symptoms, such as rash, lymphadenopathy, and thrush, were more informative. Unfortunately, none of these signs or symptoms was a highly sensitive predictor of acute infection. Rash was noted in 26.4% of acute infection visits, but it was also noted in 17.8% of noninfection visits. Thrush was associated with the highest PPV overall (62.7%). It should be noted that the predictive values for these signs and symptoms may vary in populations with different infant HIV infection prevalence, which is influenced by interventions to prevent infant HIV infection. However, even in cohorts with a very low prevalence of HIV infection, the sensitivity and specificity of these factors should remain relevant. In addition, current guidelines recommend cotrimoxazole prophylaxis for HIV-exposed infants. This study was conducted prior to these guidelines, and it is plausible that cotrimoxazole prophylaxis would alter the sensitivity and specificity of acute infection markers by decreasing infectious comorbidity in general.
A mononucleosis-like illness, generalized lymphadenopathy, and rash were associated with acute infection in a West African study that compared 22 infants who had late infection with age-matched control subjects [6
]. In our cohort, which included both infants with early infection and those with late infection, we also observed that rash and generalized lymphadenopathy were significantly more prevalent during acute infection.
We found that older infants were significantly more likely than infants <2 month of age to experience signs and symptoms during acute infection. Older infants were more likely than younger infants to have fever, cough, diarrhea, failure to thrive, difficulty feeding, dehydration, and pneumonia during acute infection. This may reflect a more mature immune system, with resulting evidence of immune response to acute HIV infection, or these symptoms may be attributable to less effective control of coinfections that could have been better contained earlier in infancy by transplacentally acquired maternal antibodies. Restricting analyses to older infants resulted in noting symptoms specific to acute HIV infection in this subset. Older infants appear to frequently experience a respiratory syndrome involving pneumonia, hospitalization, and dehydration during acute infection.
Studies involving HIV-infected adults show that acute infection syndrome is associated with a faster disease course, including accelerated mortality [3
]. We found that infants who experienced acute infection syndrome had higher plasma HIV RNA loads later in infection than did infants who did not experience symptoms during acute infection. However, we did not see an association between this syndrome and increased mortality. As reported previously, overall mortality in this cohort of HIV-infected infants was very high (>40% mortality by 24 months of age), and this mortality was attributable to several causes, some of which were unrelated to HIV infection [8
]. The high background mortality rate may have masked any potential effect of acute infection syndrome on mortality.
Our study was unique in determining symptoms associated with acute infection in both young infants <2 months of age and infants who were infected later. We used a sizeable cohort (~400 mother-infant pairs, with a 2-year follow-up period) that included infected and uninfected infants to discriminate symptoms specific for acute infection. The entire cohort of acutely infected infants provided more power to evaluate symptoms, whereas the stratified analyses of younger and older infants allowed evaluation of age-specific symptoms within these smaller strata. Limitations of the study include the fact that the interval in which to assess acute infection for in utero or intrapartum HIV infection was limited to the first 2 months of life. This narrow time-window may have limited our ability to discriminate unique acute infection–defining signs and symptoms for in utero or intrapartum HIV infection.
In this cohort of infants of HIV-infected mothers, we found that infants may manifest symptomatic illness at the time of acute infection. Signs and symptoms that were more prevalent during acute infection included rash, lymphadenopathy, and failure to thrive. Infants infected at ≥2 months of age may be more likely than others to present with pneumonia during acute infection, and they are more likely to experience symptoms, such as fever and dehydration, than are infants who are infected earlier. Acute infection syndrome in infants was not associated with increased early mortality, but it correlated with poor viral control later in infection. The presence of these signs and symptoms may serve to identify infants experiencing primary HIV infection. With expanded HAART access, awareness of acute HIV symptoms during infancy may serve to facilitate the rapid diagnosis of pediatric HIV infection and early referral for treatment.