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Progression of HIV infection in vertically transmitted disease is very rapid in early life. Worldwide, about half these children will not live to celebrate their first birthday, and majority of the rest will die before their fifth birthday. We present a rare case of a successfully managed case of AIDS in a vertically transmitted pediatric HIV disease in a 13 year old boy, a paternal orphan, lost to follow up after diagnosis in infancy and survived all these years without medical intervention , till he presented with full blown AIDS. At presentation he was in shock with severe bilateral Pneumocystis Jerovecii Pneumonia (PJP) and Herpes Simplex Type 1 Infection. He also had anemia, malnutrition and oral candidiasis. Further evaluation revealed Disseminated Tuberculosis and later systemic candidiasis . CD4 counts were 41 cells/µl. He was managed intensively. The course of illness was punctuated by non oliguric renal failure and respiratory failure. He was treated with steroids, ionotropes, oxygen Sulphamethoxazole/trimethoprim combination, broadspectrum antibiotics, Anti Tubercular Therapy (ATT), Fluconazole and later Anti Retroviral Therapy(ART). He showed improvement with a second dip in condition due to systemic candidiasis with urinary tract as the source , which was managed with Amphotericin B. He was in the hospital for about 2 months and walked out of the hospital on discharge with all his disabilities treated and under control. He is presently on follow up and leading a normal independent life today, with minor ailments off and on.
Key words: long term non progressor , Pneumocystis Jerovecii Pneumonia, HIV infection
Possibility of becoming infected with the human immunodeficiency virus (HIV) is a harsh example of the difference between being born in a developed versus being born in a developing country. In the developed world, the acquired immunodeficiency syndrome (AIDS) is a disappearing disease among children. However, new HIV infections in children continue to swell in the developing world and the majority is via the vertical route. With the development of effective prophylactic and therapeutic strategies the outlook of new pediatric HIV infection has undergone a paradigm shift in the developed world with markedly reduced the number of newly infected infants and with rosier clinical outcomes in infected children. In the USA now, the number of newly infected HIV positive infants has been pegged at less than 200 children per year and that too largely due to a failure on part or the pregnant mother to adhere to the ART regimes . Modern diagnostics can detect HIV infection in newborns as early as one month and institution of ART as per current guidelines reduces the impact of the disease spectacularly. countries.
Progression of HIV infection in vertically transmitted disease is very rapid in early life. Globally, about half these children will not live to celebrate their first birthday, and majority of the rest will die before their fifth birthday. Those lucky children who survive the first few years of life, including early serious illnesses generally remain clinically well throughout childhood, sometimes even without antiretroviral treatment. Timely institution of ART reduces the, progression to serious disease and early death is now becoming less common. When the disease afflicts adults, they leave behind orphans, many of whom may not be infected with HIV. It is estimated that by end of 2010, more than 44 million children under the age of 15 years in 34 developing nations will have lost one or both parents. Extended family is the cornerstone for care of HIV positive orphans, nevertheless these families are beleaguered by the added responsibility of these children.
Pediatric HIV represents an extraordinarily assorted group of patients, ranging from neonates to young adolescents. ART in pediatric HIV evolves from a meticulous twice-daily dosing liquid preparations to a choice of once/twice daily dosing of a single fixed-dose co formulated tablet, as the shift of age spectrum occurs from the neonatal to the adolescence group. groups.
Malnutrition and anemia in pediatric HIV is quite common. Its prevention and treatment improves survival. In children (older than 5 years) without anemia or malnutrition, a high CD4% or CD4 cell count values predict a low mortality level .anaemia.
Pneumocystis Jerovecii pneumonia is a major cause of morbidity and mortality among patients infected with the human immunodeficiency virus (HIV) and is often the first indication for starting ART. therapy.
ART has improved clinical outcomes in HIV-infected children over time as regards to mortality, time to progression to AIDS, number of opportunistic infections and organ-specific diseases. Late entry to care is associated with poorer outcomes, and earlier ART initiation should be prioritized.
We present a rare case of a successfully managed late progressor in vertically transmitted pediatric HIV disease, who is a paternal orphan , lost to follow up after diagnosis in infancy and survived till 13 years of age without any significant illness in childhood but presented with anemia, malnutrition, PJP pneumonia, Disseminated Tuberculosis, systemic candidiasis , Herpes Simplex type 1 infection and septicemic shock.
A 13 yrs old male child born in 1997 to HIV positive parents, was lost to follow up. He was not followed up after birth to confirm HIV positivity and detected to be HIV positive only in 2001 when his father died of AIDS in the same year. His mother was HIV positive during pregnancy also. He was not breast fed. Neither his mother nor he was ever on ART as treatment as not widely available in late nineties/ early part of this decade. He has an elder brother who is 18 years old and is HIV negative. He again lost to follow up after 2001 when he was once reviewed in Aug 2008. He was asymptomatic with a CD4 count of 486 cells/µl.Therafter he presented in Jan 10 with fever, cough and decreased appetite of about 4 days duration.He also had lethargy and retrosternal pain chest on coughing present of 2 days duration. There was no history of loose stools,vomiting, hemoptysis, seizures or altered sensorium.
Clinical examination revealed a malnourished, anemic child with a pulse of 112/minute, blood pressure of 94/ 60 mm of mercury right arm supine, respiratory rate of 24/minute and a temperature of 100.8°F. There was oral candidiasis, pallor , clubbing, cervical lymphadenopathy, iccthyosis over the lower limbs, HSV l type 1esions over lip and chin. There was no icterus, cyanosis or edema. Oxygen saturation was 90-92% on room air falling to 82-84% on walking for just 1-2 minutes. Facilities for arterial blood gas analysis are not available at our hospital.
Systemic examination revealed bilateral crackles both infrascapular and interscapular areas . There was hepatosplenomegaly 3 cm each with a Liver span of 15 cm. Other systems were clinically normal.
A chest x ray revealed a picture suggestive of Pneumocystis Jerovecii pneumonia. Electrocardiogram revealed incomplete right bundle branch block. On basis of the clinical picture of short duration of respiratory symptoms, tachycardia, tachypnoea, borderline hypotension, low grade fever and rapid desaturation on minimal physical work on a background of HIV positivity we started treatment on lines of PJP with supplemental oxygen, steroids (initially Injectable Hydrocortisone later converted to oral prednisolone in a dose of prednisone @ 0.6 mg/kg body weight twice daily for five days, then 0.6 mg/kg body weight daily on days 6 through 11, and then 0.3 mg/kg body weight daily on days 12 though 21), Sulphamethoxazole/trimethoprim combination(calculated @ 15mg/kg of trimethoprim daily in divided doses) and broadspectrum antibiotics (Injectable Cefotaxime, Amikacin; oral Azithromycin to cover Community Acquired Pneumonia). Induced sputum after saline nebulisation and chest physiotherapy was sent for PJP examination which came out as positive. Sputum for AFB was negative.
By next 12 hours the patient developed severe hypotension, severe sinus bradycardia-tachycardia (pulse varying from 60-180/min over minutes, clinically septicemia myocarditis) with evidence of left ventricular failure in form of increased crackles mores than 50 % lung fields. He also developed oliguric renal failure (urine output of just 100 ml in 12 hours of admission). A central line was put and with careful titration he was started on norepinephrine, dobutamine infusion, Injectable frusemide, Intravenous(IV) Morphine and IV fluids. Urinary output was restored, Lung fields cleared with settling of the left ventricular failure following settling of a stable pulse rhythm to around 90-100/min by day 3-4. Ionotropes were tapered off by day end of day 7, following stabilization of blood pressure. Supplemental oxygen was also required for about one week. Respiratory rate came down from 60/min at day one and two to 28/min by day eight. Crackles also reduced gradually and chest became clear by two weeks. Broad spectrum antibiotics were stopped by day 9. He was started on oral Fluconazole 100 mg /day for oral candidiasis by day 8. FNAC from cervical lymph nodes revealed granulomatous inflammatory picture likely tubercular. He was started on ATT by day 9 for disseminated tuberculosis (basis of diagnosis: Clinical picture, Cervical lymphadenopathy, hepatosplenomegaly and FNAC Cervical lymph node). Mantoux test was 02 mm reaction at 72 hours. Screening for hepatitis B and hepatitis C was negative. He was sitting propped up by day 8 and with gradual bedside sitting and standing by day 10 . He started walking and playing outside the ICU by day 13. The recovery was uneventful thereafter for next 2 weeks when started developing fever upto maximum of 101°F everyday with decrease in appetite and urinary burning. Urine culture grew candida albicans. He was put on Inj Amphotericin B (conventional variety, as the liposomal preparation was not available in the local market at that point of time). The fever subsided after 6 days . The appetite and urinary burning also subsided by then, however serum creatinine started rising (maximum 3.4 mg/dl) by ninth day of Injection Amphotericin B and the drug was stopped. Urine output was normal. Serum creatinine returned to normal over next couple of days. Fortunately he continued to improve on ATT and other supportive diet and vitamin supplements. CD4 counts were 41 cells/µl. ART (Zidovudine, Efavirenz and Lamivudine regime) was started by day 40 of admission (about 4.5 weeks after starting ATT). ART was torated well and recovery was uneventful thereafter. Meanwhile he had also been treated with oral and local Acyclovir for HSV Type 1 infection. He gained 04 kg weight by end of two months of hospitalization. Subsequent follow up for next 6 months, he is physically independent. He had one episode of diarrhea, managed conservatively. Repeat CD4 counts at 4 months of ART were 146 cell/µl.
HIV infection acquired via the vertical route carries a worse outcome compared with infection acquired later in childhood. Early onset of symptoms in this subgroup is also a bad prognostic factor. mortality. HIV RNA viral load reaches a zenith at around age three months, with ensuing decline thereafter which correlates with clinical progression, in vertically-infected children. Progression of the disease is also related to the levels of immunological components such as CD4, CD8 and absolute lymphocyte cell counts. During the first year of life CD4 percentage and absolute lymphocyte count independently predict rapid progression to serious disease or death and early persistent hepatomegaly or splenomegaly is a harbinger of serious disease progression thereafter.
Severe secondary infections, neurological disorders, and hepatitis account for a higher mortality rate in vertically acquired HIV infection . It is to be noted that our patient was a case of vertical transmission in view of the history as above. His disease did not progress and luckily never had any major illness throughout his childhood inspite of not being on any treatment.
The exact cause of slow or non progression of HIV disease in some children is not known. Studies in vertically acquired , pediatric long term resistant hosts have shown higher production of interleukin-2 and interferon-gamma and lower production of interleukin-10 and lower plasma viremia. The IL-10/IL-2 ratio correlates well with both CD4 counts and disease progression. Thus, these children showing resistance to disease progression are immunologically and virologically distinct from those in whom progressive HIV infection is observed. Some studies have revealed gross deletions in nef genes derived from pediatric long-term nonprogressors. Others have a higher prevalence of discrete changes that may impair some nef functions Nef. Some markers like, the delta32 CCR5 mutation can help to identify children with delayed disease progression who, consequently, may not require immediate antiretroviral treatment.It is possible that our case was a late or a non progressor . Since most of the above described tools are research based and costly , the cause of slow progression was not determined in our case.
In a study by Gautam et al on the nature of opportunistic infections in treatment naïve (not received ART) patients Pneumocystis jiroveci pneumonia was found in 45.2% patients (mostly with CD4 counts <or=100 cells/ mm) respectively. It was the presenting illness in our case also. The mortality rate amongst patients with AIDS and pneumocystis pneumonia, is 10 to 20 percent during the initial infection and substantial increase with the need for mechanical ventilation.
Effective inflammatory responses in the host are required to control pneumocystis pneumonia. Exuberant inflammation, however, also promotes pulmonary injury during infection. Severe pneumocystis pneumonia is characterized by neutrophilic lung inflammation that may result in diffuse alveolar damage, impaired gas exchange, and respiratory failure. This response is exaggerated during initial treatment with Trimethoprim-sulfamethoxazole leading to deterioration of respiratory status . This is the basis for the use of adjunctive corticosteroid therapy used to suppress lung inflammation in patients with severe infection and remains the preferred treatment. Specifically, corticosteroids are of benefit in HIV-infected patients with pneumocystis pneumonia who have hypoxemia (the partial pressure of arterial oxygen while the patient is breathing room air is under 70 mm Hg or the alveolar-arterial gradient is above 35). It is to be noted that our patient also showed a deterioration in respiratory condition with poor general status soon after starting specific therapy for PJP even though steroids were started at the onset of treatment.
Another problem encountered during the management of this case was co infection with tuberculosis and systemic candidiasis. The unstable vital parameters with respiratory failure and no oliguric renal failure inintially and later Amphotericin induced azotemia made things complicated. The patient was anemic with malnourishment which reduced the physiological reserve and immunity. This predisposed him to nosocomial infections during his long stay in hospital. ART was delayed by about 4 weeks after starting ATT even though the CD 4 T lymphocyte counts were available much before that. This was to reduce chances of Immune Reconstitution Inflammatory Syndrome (IRIS). IRIS describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of ART in HIV patients. Preexisting infections in individuals with IRIS may have been previously diagnosed and treated or they may be subclinical and later unmasked by the host's regained capacity to mount an inflammatory response.
Characteristic radiographic features of pneumocystis pneumonia are bilateral perihilar interstitial infiltrates becoming increasingly homogeneous and diffuse with progression of disease. Less commonly solitary or multiple nodules, upper-lobe infiltrates (in patients receiving aerosolized pentamidine), pneumatoceles, or pneumothorax may be seen. Rarely pleural effusions or thoracic lymphadenopathy may be seen. High-resolution computed tomography, which is more sensitive than chest radiography, may reveal extensive ground glass attenuation or cystic lesions even when chest radiographic findings are normal.
There are newer issues in HIV with longer survival in children. Emerging data suggests that there is a reduced bone mass compared to healthy peers in HIV-infected children and adolescents. With increasing survival following control of HIV infection by potent ART, it renders patients to the attainment of a reduced peak bone mass and thus to an increased fracture risk during adult life. The reduced bone mass in HIV-infected children is postulated to be the result of altered bone metabolism with increased bone resorption rate. The culprits indentified are frequent infections and use of certain antiretroviral compounds. metabolism.
The ideal situation will be 100% screening of all antenatal cases and prevent maternal to fetal transmission of HIV. With better ART and follow up , it is but expected that a larger proportion of pediatric HIV cases will survive longer. Interventions that reduce maternal viremia, are the key to predictors of child health soon after birth and will have a positive bearing on infant health outcomes in future.