CLINICAL AND BIOLOGICAL CHARACTERISTICS OF HIV-INFECTED RAPID PROGRESSOR INFANTS IN YAOUNDE – CAMEROON
Nguefack Félicitée1,2&, Koki Ndombo Paul Olivier1,2, Touffic Othman Carole Leïla1, Tejiokem Mathurin Cyrille3, Ndongo Audrey2, Ateba Ndongo Francis2, Fru Florence4, Dongmo Roger5
1 Faculté de Médecine et des Sciences Biomédicales de l’Université de yaoundé I: BP1364 Cameroun
2Mother and Child Centre of the Chantal Biya Foundation, BP 1444; Yaoundé-Cameroun
3Centre Pasteur of Cameroon,P.O. Box: 1274 Yaoundé-Cameroon
4Gynaeco-Obstetric and Paediatric Hospital-Cameroon
5District Hospital Efoulan Yaoundé-Cameroon
&Corresponding author: Nguefack Félicitée: Department of Pediatric, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, P.O. Box 1364, Yaoundé-Cameroon
Tel: 00 (237) 99 59 14 08. email
SUMMARY
Introduction: HIVinfection in some infants is marked by a rapidly progressive form which is associated with a poor prognosis due to severe clinical and biological manifestations in the first year of life. The aim of this study was to describe the clinical and biological pattern of the rapid progressors infants in a cohort ofHIV infectedchildren in apediatric center at Yaoundé.
Methodology.We carried out a retrospective study using medical files of patients aged less than 12 months, at clinical stage 4, or those with CD4 count <25%, whatever their clinical stage.
Results.We recruited 150 rapid progressors. Their PCR tests were performed mostly after 3 months of age, with a median age of 6 months at the first test. HIV-related recurrent and chronic signs and symptoms were found in 83.3% of patients. Co-morbidities were predominantly malnutrition (74.6%), acute gastroenteritis (61.3%), oral thrush (60.0%), pulmonary (43.3%) and skin infections (29.3%). Stunting, underweight and wasting were present in 42.6%, 74.6% and 58.6% of infants respectively. The mean viral load was 14609 492 copies/ml. Anemia was present in 99.1% of the subjects.
Conclusion. Most of the clinical signs found in the rapid progressors infants were those current during childhood illnesses. Meanwhile, their recurrence and chronicity were unusual and could orientate towards early diagnosis of HIV when the child status is unknown.
Keywords: HIV/AIDS, rapid progressors, infants, symptoms, paraclinicalsigns.
INTRODUCTION
The clinical manifestation of HIV infection in children depends on when the child was exposed to the virus(1,2). The HIV causes immune deficiency, especially a CD4 lymphocytopeniawithin a few months or years. The severity of the disease has been classified by the WHO(3) and the CDC Atlanta (4)into clinical and immunologicalstages. Rapid progressors develop AIDS-defining conditions or sever immune deficiency in their first year of life(1,2,5). At birth, their immune systems are under-developed(6), thereby exposing them to these severe conditions. In Cameroon, the HIV status of most infants of seropositive mothers still remains unknown(7,8). Not all are followed up, in spite of the Prevention of Mother to Child Transmission (PMTCT) program(9). The diagnosis could be delayedin these children not followed up because clinical signs related to HIV only manifest at an advanced stage of infection. Nevertheless, 85% of infants are eligible for antiretroviral therapy within the first 6 months of life(10). The clinical presentation of HIV infection is rather non-specific. The signs can be found both in infected and uninfected children(11).In the former, they are particularly severe and recurrent(11), sometimes atypical, suggested of the diagnosis.These are usually pneumonia, diarrhoea and invasive infections like sepsis(12). Pneumonia and diarrhoea are amongst the main causes of death in HIV-infected children in whom death occurs at a median age of about 6 months(13). Such signs must be easily recognizable by any health worker, whatever the level of the health system at which he works. Early diagnosis and treatment of HIV infection are crucial for the survival of patients(1,14,15). The aim of our study was to describe the clinical and paraclinical of rapid progressors to permit early diagnosis and treatment.
POPULATION AND METHOD
We carried out a descriptive and retrospective study on HIV-infected rapid progressors infants at the Mother and Child Centre of the Chantal Biya Foundation (MCC-CBF) from January 2010 to February 2012. The MCC-CBF is a pediatric center which caters for the largest cohort of children on ARVs in Cameroon. The patients are referred to this centre for diagnosis or management of an already diagnosed HIV-infection. Others are referred for the further implementation of PMTCT measures. This study was approved by the Institutional Ethics and Research committee of the Faculty of Medicine and Biomedical Sciences of the University of Yaoundé I.
Rapid progressors are defined as children aged 2 years or less who developed a severe immune deficiency with a CD4 count <25% or an AIDS definingcondition during their first year of life or both(1,16). We excluded asymptomatic HIV-infected patients or those whose CD4 counts were unavailable. Only rapid progressors less than12 months old were included in this study. HIV infection in our study siteis diagnosed in infantsusing genomic amplification of viral RNA (PCR). The patients are treated following national guidelines. The PCR was carried out at the Centre Pasteur du Cameroun with the financial supportof thePediacam project(7) and at the Chantal Biya International Research Center (CIRCB)(17).
We reviewed the medical records of all our patients, whether they were on ARV treatment or not. We collected informationontheir past medical history with regards topresenting symptoms, their recurrence, the duration, the history of hospital admissions and reported diagnoses. Their nutritional status was evaluated with using WHOcriteria. These included the Z-score of weight-for-height, weight-for-age, and height-for-age; defining emaciation, global weight insufficiency, growth retardation or chronic malnutrition. We evaluated the head circumference for age with the aim ofestimating the psychomotor development(2). These anthropometric measures were interpreted with the WHO-Anthro version 3.2.2(18). We also looked for anaemia which was defined as a haemoglobin level <11g/dl for children less than 1 year of age(19).
STATISTICAL ANALYSIS
Categorical variables with regard to clinical and biological characteristics of the subjects weredescribedaccording to frequencies and percentages. The mean and median were used for the continuous variables with a confidence interval of 95%.
RESULTS
The study was carried out on 150 rapid progressors, more than half (87 out of 150 subjects representing 58%) of whom were already in clinical stage 4 at the time of recruitment (Table I). The sex ratio was 1.02. The median age of the patients was 6 months, the youngest being 2 months old. About3/4of the patients (72.7%) had received all their EPI vaccines whereas 2.67% had not. Most of them, 123 (82.0%) were referred from others health units of the site of study. The median duration of hospitalisation was 22 days with an interquartile range of [30 - 67 days].
Table I: Distribution of rapid progressors infants selected with regard of the clinical and immunological stages
clinical Stage / Immunological classification(Immune depression)
Unknown / A / B / C / D / Total
1 / 0 / 0 / 0 / 0 / 13 / 13
2 / 0 / 0 / 0 / 0 / 7 / 7
3 / 0 / 0 / 0 / 0 / 43 / 43
4 / 25 / 4 / 3 / 5 / 50 / 87
Total / 25 / 4 / 3 / 5 / 113 / 150
A= Not significant % CD4 > 35; B= Moderate 30 <% CD4 <35; C= Important 25 < % CD4 < 30; D= Severe % CD4 <25
Past medical history
The birth weights ranged from 1.3 to 5kg with a mean weight of 3.1kg. In 14% of cases, it was less than 2.5kg and in 69% of subjects, it ranged from 2.5 to 5 kg. In 16.7% of patients the birth weight was unknown. Some (21.3%) had been hospitalized in the neonatal period for prematurity, neonatal infection or asphyxia (62.5%, 34.4% and 3.1% respectively). Beyond this period, 42.7% of the children had been hospitalized at least once; the mean number of hospital admissions was 1.5. The reasons are presentedin Figure 1.
Most patients (83.3%) had had recurrent or chronic symptoms before being admitted in our Site. We used the 2010 WHO classification to group them (Figure 2). Long-standing fever was the most recurrent sign found in our patients.
Figure 1: Reasons of previous hospitalisations of the rapid progressors infants beyond the neonatal period
Figure 2: Previous recurrent or chronic symptoms in the rapid progressors infants
Clinical presentation on admission in our site of study
The anthropometric values of height-for-age, weight-for-age and weight-for-height were less than -2 Z-score in 42.6%, 74.6% and 58.6% respectively in the infants. These represented stunting, underweight and wasting for which 14%, 56% and 42% presented the severe forms respectively. The median head circumference (HC) was 42.1 cm. It was less than 2-Z-score in 64 (31.3%), 19 of whom (12.9%) had severe microcephaly with a HC-for-age less than -3Z-score.
Signs and symptoms observed
The clinical manifestations were varied. Cough was the major symptom (72.0%). The principal diagnoses reported were malnutrition, acute gastroenteritis, oral thrush, skin and respiratory infections(Tables II and III).
WHO immunological, virological and hematological characteristics at the time of diagnosis of HIV in rapid progressors infants
About 90% of the patients, had a severe immune deficiency with a CD4 count <25%. More than 4/5th of the viral loads available in 79 patients were >1,000,000 copies/ml with 48.1% having a viral load >5million copies/ml (Table IV). Most of the PCR tests were carried out at an age of more than 3 months, the median age of the children during the first screening was 6 months. Anaemia with a mean haemoglobin level of 8.6g/dl was present in 121 (99.1%) patients who had an available full blood count. In 20.6% of these infants, it was severe and needed blood transfusion.
Tableau IV: Distribution of rapid progressors with regard of the immunological (OMS) classification and the viral load
CD4 (%) / N / (%)Immunedepression (n=125) / Severe / 0-24 / 113 / 90.4
Important / 25-30 / 5 / 4.0
Moderate / 31-35 / 3 / 2.4
Not significant / > 35 / 4 / 3.2
Viral load (n=79) / < 100 000 / 2 / 2.5
100000- 1000 000 / 10 / 12.7
> 1000 000 / 67 / 84.8
Table II: Signs and symptomspresented by patients with regards tothe system involved
Signs and symptoms / N / (%)General state / Altered / 108 / 72.48
Dehydration / Light / 26 / 17.45
Moderate / 42 / 28.19
Severe / 29 / 19.4
Digestive system / Oral thrush / 90 / 60.0
Diarrhea / 88 / 58.7
Vomiting / 68 / 45.3
Hepatomegaly / 49 / 32.7
Respiratory system / Caught / 108 / 72.0
Abnormal vesicular murmurs / 80 / 53.3
Respiratory distress / 32 / 21.3
Cyanosis / 6 / 4.0
Tegument lesions / Nappy rash / 31 / 20.7
Papules / 30 / 20.0
Macules / 9 / 6.0
Pustules / 21 / 14.0
Ulcerations / 20 / 13.3
Vesicles / 19 / 12.6
Pruritus / 43 / 28.67
Squama / 17 / 11.3
Hematopoietic system / Pallor / 66 / 44.0
Jaundice / 2 / 1.3
Polyadenopathy / 57 / 38.0
Splenomegaly / 34 / 22.7
Cardiovascular system / Tachycardia / 85 / 56.7
heart murmur / 12 / 8.0
Edema / 3 / 2.0
Gallop rhythm / 2 / 1.3
ORLsystem / Rhinorrhea / 69 / 46.0
Ears discharge / 8 / 5.3
Congestive eardrums / 6 / 4.0
Neurologicalsystem / Irritability / 11 / 7.3
Convulsions / 9 / 6.0
Bulging fontanel / 7 / 4.7
Hypotonia / 5 / 3.3
Psychomotor regression / 19 / 12.67
Psychomotor retardation / 34 / 22.67
Tableau III: Diagnosis recorded in rapid progressors infants
Diagnostic / N / (%)Malnutrition / 112 / 74.6
Acute gastroenteritis / 92 / 61.3
Oral thrush / 90 / 60.0
ARI* / 66 / 44.0
Pneumonia / 65 / 43.3
Skin infection / 59 / 39.3
Bronchitis / 50 / 33.3
Anemia / 36 / 24.0
Malaria / 22 / 14.7
Otitis / 14 / 9.3
Pulmonary tuberculosis / 11 / 7.3
UTI** / 7 / 4.7
Meningitis / 6 / 4.0
Conjunctivitis / 1 / 0.7
*ARI= Acute upper respiratory tract infection, **UTI= Urinary tract infection
DISCUSSION
RecognizingHIV infectionin infantsfrom theseverity andrecurrence of certainsigns and symptomsis necessary for the early identification ofrapid progressorsin thecontext where the PMTCT measures are not properly administered. The authors describe theconditions and pathologies that HIV-infected rapid progressors infants presented before or during theirenrolmentinto the study. They also looked for their immunological, virological and hematological characteristics at the time of diagnosis of HIV.
Despite the similarity in the clinical presentation of HIV infection to that of other childhood illnesses(20), they are a valuable aid in the diagnosis of HIV infection. The diagnosis was made late for the rapid progressors infants in this study, in whom the PCR tests were done well beyond the WHO-recommended ages. This observation was also made in other studies(21), although their PCR were performed much earlier, at a median age of 8.3 weeks(22). It is rare for HIV infected infants to remain asymptomatic during the first year of life(23,24). About 85% of these patients present severe clinical signs and symptoms within the first 6 months(10,23,25). The signs which classified them as severe infection according to the CDC were described by some authors at a median age between 9 and 12 months(12). In a study conducted in Bangkok, the median age at which patients were classified as being rapid progressors, either because they presented severe conditions attributable to AIDS or because they died early, was 9 months(11). In our study, the median age of rapid progressors was 6 months and 83.3% of the patients had had severe or recurrent symptoms (Table II). The main symptoms were long-standing fever, weight loss, persistent cough and diarrhoea.These characteristics were reported in other studies as well(25,26). Most of the signs could easily be recognised by any health officer who implementsIMCI guidelines(27,28); which are knownto be an efficient strategy for the diagnosis and management of HIV-infected children in resource limitedsetting like ours.
As concerns physical signs, mouth thrush, multiple lymphadenopathies, hepatomegaly and splenomegaly were the most common in our study. Some authors have shown that the presence of the last three signs that is lymphadenopathies, hepatomegaly and splenomegaly, in newborns is a marker of rapid evolution to stage C of HIV infection(16). Moreover, a low birth weight and a head circumference less than the normal values were noted in the rapid progressors infant(2,16). Encephalopathy is also very common in infants infected with HIV(29,30), it being described in most of these rapid progressors infants(16,31,32). In the cohort of Cooper et al in 1998, 21% developed encephalopathy during a 24 month follow-up; they had atleast a moderate immune deficiency according to the CDC classification(33). Neuro-developmental disorders are predictive of death in infected infants who have survived until 4 months(2). In this study, 35.54% of patients had developmental abnormalities of whom 22.7%had psychomotor growth retardation and 12.7%had loss of already-acquired function. Our low values do not reflect the scarcity of HIV encephalopathy in our milieu. In general, most severe conditions like malnutrition and severe infections cancause psychomotor regression(34,35), which we found in most of our patients. Other neurologicaldisorders were not systematically sought by the health personnel. Moreover, morphologicalinvestigations like Computed Tomography scans and Magnetic Resonance Imaging are not done systematically in children presenting with neurologicaldisorders in our setting. The low financial mean of the parents and the high cost of these investigations limit their use.
Like in other African and European studies(20), malnutrition, pneumonia and gastroenteritis were the most frequently diagnosed in our study (Table III). Severe malnutrition is due to complex mechanisms. Besides pathologies, the effectof HIV itself takes on the nutritional state, oral thrush is one of the major factors responsible for malnutrition(36). Regarding pneumonia, a study carried out in Texas, had showed significant alterations in the lung function of rapid progressors infants(37).
As regards the virological and immunological aspects, the clinical stage of the patients was not always correlated with their biological status. It has been shown that child can have a good clinical state in spite of a severe immune deficiency(38). Hence, among the patients we recruited because of their CD4 counts were less than 25%, 20 (13.3%) were in clinical stages 1 and 2, 13 of whom were asymptomatic. In a like manner, not all of those recruited in clinical stage 4, were severely immune depressed; in some it was moderate and even not significant (table I). This was not shown in others studies(5,39).
Our selection of patients with low CD4 count would have introduced a bias into the study because 113 (90.4%) of the 125 CD4 registered, showed severe immune depression. This percentage is however close to the 91.7% found by other authors(40). As concerns the viral load, it was very high in our patients, the highest being 110 million copies/ml in a 3-month old infant. Studies have shown peak viral loads of 5,160,000 and 984,000 copies/ml at 1 and 2 months of life, respectively(10,41). In infants, high viral loads are associated with a rapid progression of the disease. According to some authors, it is associated to death within the first six months of life(42). However, this association between CD4 count, viral load and stage of the disease were not found elsewhere(43).
As concerns other biologicaldisorders, the majority (99.1%) of the rapid progressors had anaemia in our study, 20.6% had a hemoglobinemia <7.5 g/dl. Anemia is frequently described in infected patients(44–46). HIV infection, prematurity and low birth-weight <2,500grams increases the risk of anaemia(45). It is also a marker of rapid progression to AIDS and is independently associated with ahigher risk of death(38).The anaemia can also be due to multi-deficiency nutritional disorders, and some co-morbidities such as malaria(47).
CONCLUSION
Rapid progressors were diagnosed late in our study. Most of them were not being followed up according to the programme of the PMTCT of HIV. In this context, the recognition of clinical characteristics of rapid progressors is an asset for the early diagnosis approach and treatment of these patients. Most of the signs we found were characteristic due to their recurrence and chronic nature. Another study with a cohort of children followed up from birth will ascertainthe exact age at which clinical and biologicaldisorders appear in children in our milieu.
CONFLICTS OF INTEREST
This study was not financed in any way. The authors agreed that there is no conflict of interest.
Authors’ contribution:NF initiated the thesis subject, the synthesis of which gave rise to this publication she enriched the discussion. DR drafted the initial document;TOCL collected data and wrote this thesis for a doctorate in general medicine. KNPO supervised this thesis; it proofread and corrected the draft.TMcorrected and enriched the statistical analysis and the discussion. NA and ADF followed up the patients.
Acknowledgment: The authors thank all the staff of the unit ofHIVmanagement of the MCC-CBF for their support, as well asthe laboratories of the CPC and CBIRC as well. They also wish to thank the statistician and the translator of the document from French to English.
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