Persistent Fever, Hypoxemia, and Respiratory Distress in a 3-Month-Old Infant

Abstract

A 3-month-old term boy with adequate prenatal care, no complications during pregnancy, and no significant medical history initially presents to a local hospital with fever. He is diagnosed as having Escherichia coli pyelonephritis, receives 3 doses of ceftriaxone in-hospital, and is discharged to complete a 14-day course of cephalexin. He continues to have intermittent fevers and is increasingly irritable while taking cephalexin (measured up to 101 °F [38.3 °C] at home). Thirteen days after his initial presentation, he returns to the emergency department with fever (102.3 °F [39.1 °C]), sleepiness, and altered mental status. He is found to have hypoxemia (pulse oximetry in the 70s on room air) and lethargy. On hospitalization to the local hospital, he has tachypnea and retractions, and he continues to require oxygen by nasal cannula. A nasogastric tube is placed due to poor feeding. Findings from respiratory viral testing, blood and urine cultures, cerebrospinal fluid studies, chest radiography (CXR), abdominal ultrasonography, upper gastrointestinal series, and magnetic resonance imaging of the head and neck are normal. Echocardiography demonstrates normal biventricular function and a small patent foramen ovale. With persistent oxygen requirement, progressive respiratory distress, and possible infiltrate vs atelectasis on repeated imaging, he is started first on ampicillin, and then on ceftriaxone and acyclovir, with no significant improvement.He is now transferred to a children’s hospital for further evaluation. He is afebrile, with oxygen saturation of 100% on 2 L of oxygen by nasal cannula, with tachypnea (56 breaths/min) and a normal heart rate (128 beats/min) with regular rhythm. Physical examination is pertinent for tachypnea with intercostal retractions, abdominal breathing, and a palpable liver edge 2 to 3 cm below the right costal margin; breath sounds are clear. Attempts to wean off oxygen fail, with desaturations to the 80s. CXR demonstrates bilateral central patchy opacities (Fig). Findings from evaluations include a white blood cell count of 4200/μL (4.2 × 109/L); absolute neutrophil count, 1300/μL (1.3 × 109/L); absolute lymphocyte count, 2400/μL (2.4 × 109/L); hemoglobin level, 9.7 g/dL (97 g/L); platelet count, 201 × 103/μL (201 × 109/L); alanine aminotransferase level, 92 U/L (1.54 μkat/L); and aspartate aminotransferase level, 274 U/L (4.58 μkat/L). Normal values for age are displayed in Table 1. Respiratory pathogen panel is positive for human metapneumovirus and negative for adenovirus, influenza and parainfluenza viruses, respiratory syncytial virus, rhinovirus/enterovirus, coronavirus, Chlamydia pneumoniae, and Mycoplasma pneumoniae. Polymerase chain reaction (PCR) for Bordetella pertussis is negative. Additional infectious disease testing reveals the diagnosis.The patient’s fevers, hypoxemia, respiratory distress, and CXR findings suggested a viral or atypical infectious etiology at presentation. Common respiratory viruses (such as respiratory syncytial virus, influenza) were considered, and human metapneumovirus was detected. Elevated liver enzyme levels could be seen in association with a viral infection (such as Epstein-Barr virus or cytomegalovirus [CMV]), with an atypical infection, or with sepsis. Blood and cerebrospinal fluid cultures were negative at presentation. Congenital heart disease (such as tetralogy of Fallot or transposition of the great arteries) was ruled out on echocardiography. Upper gastrointestinal series was negative for reflux/aspiration. The patient’s severity and duration of symptoms, with a prolonged 2-week course of a progressive respiratory illness with fevers, irritability, and hypoxic events, prompted hospital transfer and an expanded evaluation. Given the prolonged course and worsening respiratory status, this included consideration of an abnormal immune system and the possibility of an opportunistic infection.Testing for HIV by combined HIV-1/2 antibody-antigen test was positive. HIV viral load was greater than 16.7 million copies/mL, and CD4 count was 199 cells/μL (8%), signaling advanced HIV. Bronchoalveolar lavage (BAL) was subsequently performed to evaluate for opportunistic infection; the infant later required intubation for respiratory failure. BAL fluid was positive for Pneumocystis jirovecii by PCR and silver stain. BAL fluid studies were also positive for CMV by viral culture, and CMV was detected in serum by PCR, at 50 900 copies/mL. BAL fluid was additionally positive for human metapneumovirus by PCR. The infant was diagnosed as having advanced perinatal HIV complicated by P jirovecii pneumonia (PJP), CMV pneumonia and viremia, and human metapneumovirus.The infant’s mother had a negative first-trimester HIV test; she did not have a repeated HIV test before delivery. The Centers for Disease Control and Prevention (CDC) recommendations for repeated testing in the third trimester are limited to specific circumstances: in geographic areas with higher HIV prevalence, among women with known risk factors for acquiring HIV, or in states where third-trimester testing is required.1,2 In this case, geographic criteria or state policy did not compel repeated testing, and maternal risk factors for HIV were not apparent during pregnancy. The infant was vaginally delivered and exclusively breastfed. Due to the subsequent diagnosis of HIV in the infant, HIV testing was performed for the mother and her partner; both tests were positive. Both individuals were referred to HIV care providers.Global estimates are that 1.3 million people living with HIV become pregnant annually, and that 3 million children are living with HIV.3,4 Pediatric HIV is typically due to perinatal transmission. Without antiretroviral therapy (ART) or prophylaxis, the rate of transmission during pregnancy, labor and delivery, or breastfeeding ranges from 15% to 45%.3,5 Since the availability of effective ART, the incidence of perinatal HIV transmission in the United States has decreased from 42.8 cases per 100 000 infants in 1991 to 1.3 cases per 100 000 infants in 2015.3,6 Perinatal HIV is associated with a more rapid clinical decline than that seen in adults who acquire HIV. Before the availability of effective ART for infants, perinatal HIV was associated with 50% mortality by age 2 years.7 Some children with untreated perinatal HIV survive into later childhood or adolescence before being diagnosed as having HIV after developing late manifestations and/or opportunistic infection(s). This can occur for children with slower progression of HIV.Infants with perinatal HIV are susceptible to PJP, with the highest incidence during the first year after birth, particularly between ages 3 to 6 months.8 PJP is an opportunistic infection affecting immunocompromised populations, marked by fever, fatigue, significant hypoxemia, dyspnea, tachypnea, and cough. Onset may be indolent or acute, with a range of clinical severity at presentation.9 CXR may demonstrate bilateral perihilar or diffuse parenchymal infiltrates, or may appear normal early in the course of illness.9,10 Prolonged hypoxemia warrants further investigation with BAL to evaluate for atypical or opportunistic infections such as PJP. PJP is diagnosed by visualization of Pneumocystis cysts on a respiratory specimen; with BAL being the diagnostic procedure of choice.9,10 In clinical scenarios where PJP is highly suspected but not yet confirmed in an immunocompromised patient, empirical treatment may be considered while evaluations are pending.Additional possible manifestations of perinatal HIV in infants and children may include gastrointestinal infections, respiratory illnesses, growth delays and stunting, lymphadenopathy and parotitis, serious and recurrent bacterial infections, and opportunistic infections.11 Common opportunistic infections include PJP, tuberculosis, candidiasis, CMV, herpes simplex virus, varicella, toxoplasmosis, and others.8,12 Cryptococcal infections are uncommon in early childhood but increase in incidence in later childhood and adolescence.8This case signals missed opportunities for prevention and diagnosis of perinatal HIV. HIV testing should be performed early in pregnancy. Many, but not all, states additionally require third trimester HIV testing. Identified risk factors, such as sexually transmitted infections, multiple sexual partners, use of intravenous (IV) drugs, or having a partner living with HIV with detectable viral load, should prompt repeated HIV testing in the third trimester or at delivery. Maternal seroconversion during pregnancy is a major risk factor for perinatal HIV transmission.In the United States, although perinatal HIV transmission is increasingly rare, perinatal transmission continues to occur and is characterized by wide racial and ethnic disparities. In 2020, approximately 40 infants acquired HIV in the perinatal period.13 All newborn infants should have maternal HIV status determined at delivery; in cases where the mother is not available or not willing to be tested, infants should undergo HIV antibody testing.13 If positive, the infant should receive HIV diagnostic testing and prescribed antiretroviral medications, in accordance with federal guidelines.13Perinatal HIV transmission occurs during pregnancy, delivery, or breastfeeding. Risk of HIV transmission is influenced by maternal HIV viral load during this period. Infants considered at high risk include those whose mothers did not receive antepartum ART; received only intrapartum ART; received antepartum ART but did not achieve viral suppression within 4 weeks before delivery; or experienced primary or acute HIV during pregnancy or breastfeeding (Table 2).13 For newborns at high risk for HIV, current US federal guidelines recommend initiating a 3-drug ART regimen of zidovudine, lamivudine, and either raltegravir or nevirapine as soon as possible after delivery (ideally within 6 hours); this serves both as presumptive treatment and as prophylaxis.13 Clinicians must refer to US federal guidelines directly for current recommendations because these are continuously updated based on evidence, including for antiretroviral dosing based on gestational age and weight.13 Additional support is available through the National Clinician Consultation Center for Perinatal HIV/AIDS, accessible for phone consultations at (888) 448–8765.14Infants with confirmed or indeterminate HIV status should be started on trimethoprim-sulfamethoxazole for PJP prophylaxis at 4 weeks of age.9 Criteria to consider discontinuation of trimethoprim-sulfamethoxazole prophylaxis include age 12 months or older, with a CD4 count of 500 cells/μL or greater and a CD4 percentage of 15% or greater after receipt of ART for 6 months or longer.9PJP is managed with treatment dosing of trimethoprim-sulfamethoxazole, typically through IV administration, for a 21-day course, with attention to possible adverse reactions to therapy.9,10 A corticosteroid course should also be initiated within 72 hours of diagnosis if infants have moderate to severe PJP because there is the potential to decrease acute respiratory failure, ventilation needs, and mortality.9,10 Mortality ranges from 5% to 40% in patients treated for PJP.10 Co-infection with other organisms (eg, CMV) is associated with more severe disease.9,10The infant was hospitalized for 7 weeks, during which he was started on IV trimethoprim-sulfamethoxazole and corticosteroids for treatment of PJP and on ART (initially with abacavir, lamivudine, and raltegravir [all dosed twice daily]). Azithromycin (dosed weekly) was started for prophylaxis against Mycobacterium avium complex. The infant’s course was complicated by a prolonged PICU admission with respiratory failure, acute respiratory distress syndrome, and immune reconstitution inflammatory syndrome, requiring mechanical ventilation, high-frequency oscillator, and prone positioning. Evaluations included tests for infection with syphilis, hepatitis B, herpes simplex virus, Cryptococcus, Toxoplasma, and Histoplasma, which were all negative. CMV pneumonitis/viremia was treated with IV ganciclovir and transitioned to oral valganciclovir. He had no evidence of CMV retinitis. During the hospitalization, HIV viral load declined to 34 700 copies/mL and CD4 count improved to 518 cells/μL (39%). Corticosteroid dosing was tapered. On completion of the 21-day course of treatment, trimethoprim-sulfamethoxazole was given at prophylaxis dosing. He continued taking ART and had close follow-up with pediatric HIV specialists, with attainment of viral suppression and healthy clinical status.Maternal HIV acquisition during pregnancy or breastfeeding is associated with significantly elevated risk of perinatal HIV transmission.Clinicians evaluating acutely ill infants should be aware of the potential for undiagnosed perinatal HIV infection, including instances when maternal testing for HIV is negative in the first trimester.Infants with perinatal HIV typically have an accelerated course of illness and progression to opportunistic infections, highlighting the importance of timely diagnosis and treatment. Pneumocystis jiroveci pneumonia is a common initial presentation for perinatally infected infants, in addition to gastroenteritis, recurrent bacterial infections, and impaired growth.