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

Presentation

A three-month-old full-term male infant with adequate prenatal care, no complications during pregnancy, and no significant past medical history initially presents to a local hospital with fever. He is diagnosed with E. coli pyelonephritis, receives three 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 on cephalexin (measured up to 101°F at home). Thirteen days from his initial presentation, he returns to the emergency department with fever (102.3°F), sleepiness, and altered mental status. He is found to have hypoxemia (pulse oximetry in 70s on room air) and lethargy. On hospitalization to the local hospital, he has tachypnea and retractions, and 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 X-ray (CXR); abdominal ultrasound; upper gastrointestinal series; and magnetic resonance imaging of head and neck are normal. Echocardiogram demonstrates normal biventricular function and a small patent foramen ovale. With persistent oxygen requirement, progressive respiratory distress, and possible infiltrate vs. atelectasis on repeat 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 100% while on 2L oxygen by nasal cannula, with tachypnea (56 breaths/min) and normal heart rate (128 beats/min) with regular rhythm. Physical exam is pertinent for tachypnea with intercostal retractions, abdominal breathing, and a palpable liver edge 2–3 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 (Figure 1). Findings from evaluations include white blood cell count 4.2 × 10⁹/L; absolute neutrophil count 1.3 × 10⁹/L; absolute lymphocyte count 2.4 × 10⁹/L; hemoglobin 9.7 g/dL; platelets 201 × 10⁹/L; alanine transaminase 92 Units/L; and aspartate aminotransferase 274 Units/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 (RSV), rhinovirus/enterovirus, coronavirus, Chlamydia pneumoniae and Mycoplasma pneumoniae. Polymerase chain reaction (PCR) for Bordetella pertussis is negative. Additional infectious disease testing reveals the diagnosis.

Figure 1.

Chest x-ray for this three-month-old infant presenting with fever, hypoxemia, and respiratory distress.

Table 1.

Ranges of normal laboratory values for three month-old infant.^a

Laboratory test	Range of normal laboratory values for age
White blood cell count	6.0 – 18.0 × 109/L
Absolute neutrophil count	1.1 – 7.7 × 109/L
Absolute lymphocyte count	2.7 – 13.5 × 109/L
Hemoglobin	10.4 – 16.0 g/dL
Platelets	150 – 450 × 109/L
Alanine transaminase	7 – 52 Units/L
Aspartate aminotransferase	13 – 39 Units/L

^a,Normal reference ranges are as reported by the performing laboratory.

Discussion

Differential 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 RSV, influenza) were considered and human metapneumovirus was detected. Elevated liver enzymes 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 two-week course of a progressive respiratory illness with fevers, irritability, and hypoxic events, prompted hospital transfer and an expanded work-up. Given the prolonged course and worsening respiratory status, this included consideration of an abnormal immune system and the possibility of an opportunistic infection.

Actual Diagnosis

Testing for human immunodeficiency virus (HIV) by combined HIV-1/2 antibody-antigen test was positive. HIV viral load was >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 with advanced perinatal HIV, complicated by Pneumocystis 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 repeat HIV test prior to delivery. US Centers for Disease Control (CDC) recommendations for repeat 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 repeat 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 were referred to HIV care providers.

The Condition

Global estimates are that 1.3 million people living with HIV become pregnant annually, and that three 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 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. Prior to the availability of effective ART for infants, perinatal HIV was associated with 50% mortality by the age of two years.⁷ Some children with untreated perinatal HIV survive into later childhood or adolescence before being diagnosed with 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 of life, particularly between the ages of 3–6 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, empiric 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 (HSV), varicella, toxoplasmosis, and others.^8,12 Cryptococcal infections are uncommon in early childhood, but increase in incidence in later childhood and adolescence.⁸

This 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 repeat 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, while perinatal HIV transmission is increasingly rare, perinatal transmission continues to occur, and is characterized by wide racial and ethnic disparities. In 2020, about 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.¹³

Treatment/Management

Perinatal 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 didn’t receive antepartum ART; received only intrapartum ART; received antepartum ART but didn’t achieve viral suppression within 4 weeks prior to delivery; or experienced primary or acute HIV during pregnancy or breastfeeding (Table 2).¹³ For newborns at high risk of HIV, current US federal guidelines recommend initiating a three-drug ART regimen of zidovudine, lamivudine, and either raltegravir or nevirapine as soon as possible after delivery (ideally within 6 hours); this serves as both presumptive treatment and as prophylaxis.¹³ Clinicians must refer to US federal guidelines directly for current recommendations, as 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) 448–8765.¹⁴

Table 2.

Summary of current US Department of Health and Human Services guidelines for antiretroviral management of infants with perinatal HIV exposure or infection. Directly adapted from: Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States. US Department of Health and Human Services. 2003. Available at https://clinicalinfo.hiv.gov/en/guidelines/perinatal. Accessed October 28, 2023. Table 10.^a

	Description	Neonatal antiretroviral management considerations13
Consultation and resources	Clinicians should follow the current perinatal HIV guidelines from the US Department of Health and Human Services,13 which are continuously updated as new evidence and expert recommendations emerge. For up-to-date guidelines, including detailed recommendations regarding infant HIV testing, antiretroviral management and dosing, and feeding considerations, see https://clinicalinfo.hiv.gov/en/guidelines/perinatal/.13 Clinicians should also consult with pediatric HIV experts in their setting regarding the evaluation and management of infants with perinatal HIV exposure or infection. Additional support is available through the National Clinician Consultation Center for Perinatal HIV/AIDS, accessible for phone consultations, at (888) 448–8765.14
Low risk of perinatal HIV transmission	Infants ≥37 weeks gestation, when the mother… Is currently receiving and has received at least 10 consecutive weeks of ART during pregnancy, and Has achieved and maintained or maintained viral suppression (≥2 consecutive tests with HIV RNA levels <50 copies/mL obtained ≥4 weeks apart) for the remainder of the pregnancy, and Has HIV RNA <50 copies/mL at or after 36 weeks and within 4 weeks of delivery, and Did not have acute HIV infection during pregnancy, and Has reported good ART adherence, and adherence concerns have not been identified.	Zidovudine for 2 weeksb
	Infants born to mothers who do not meet the criteria above or the criteria for high risk below, but who have HIV RNA <50 copies/mL at or after 36 weeks gestation	Zidovudine for 4 to 6 weeksb
	Premature infants (<37 weeks gestation) who are not at high risk of perinatal acquisition of HIV	Zidovudine for 4 to 6 weeksb
High risk of perinatal HIV transmission	Mothers who did not receive antepartum ARV drugs, or Mothers who received only intrapartum ARV drugs, or Mothers who received antepartum ARV drugs but did not have viral suppression (≥2 consecutive tests with HIV RNA levels <50 copies/mL obtained ≥4 weeks apart) within 4 weeks prior to delivery, or Mothers with acute or primary HIV infection during pregnancy or breastfeeding (in which case, breastfeeding should be immediately discontinued)	Presumptive HIV therapy,b using either: Zidovudine, lamivudine, and nevirapine (treatment dose), or Zidovudine, lamivudine, and raltegravir administered together from birth to 2–6 weeks; if the duration of the 3-drug regimen is shorter than 6 weeks, zidovudine should be continued alone, to complete a total of 6 weeks of prophylaxis.b
Presumed newborn HIV exposure	Mothers with unconfirmed HIV status who have at least one positive HIV test at delivery or postpartum, or Mothers whose newborn has a positive HIV antibody test	ARV management as described above for newborns with a high risk of perinatal HIV acquisition Infant ARV drugs should be discontinued immediately if supplemental testing confirms that the mother does not have HIV
Newborn with HIV	Positive newborn HIV virologic test	Three-drug ARV regimen using treatment doses. Refer to US DHHS Pediatric Antiretroviral Guidelines for specific treatment recommendations15

Abbreviations: ARV, antiretroviral; DHHS, Department of Health and Human Services; HIV, human immunodeficiency virus.

^a,It is critical to note that US Perinatal HIV guidelines are updated continuously. Therefore, while this table presents an overview of the current recommendations as of the time of this writing, clinicians must always refer to the guidelines directly (at https://clinicalinfo.hiv.gov/en/guidelines/perinatal/)¹³ for current recommendations, including for infant HIV testing, antiretroviral medication management, and feeding considerations.

^b,Please refer directly to the US perinatal HIV guidelines (at the web address above) for details and latest evidence-based recommendations.¹³

Infants with confirmed or indeterminate HIV status should be started on trimethoprim-sulfamethoxazole for PJP prophylaxis, starting at four weeks of age.⁹ Criteria to consider discontinuation of trimethoprim-sulfamethoxazole prophylaxis include age ≥12 months, with CD4 count ≥ 500 cells/μL and CD4 percentage ≥ 15% after receipt of ART ≥6 months.⁹

PJP 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, as there is potential to decrease acute respiratory failure, ventilation needs, and mortality.^9,10 Mortality ranges from 5–40% in patients treated for PJP.¹⁰ Co-infection with other organisms (e.g., CMV) is associated with more severe disease.^9,10

Patient Course

The infant was hospitalized for seven weeks, during which he was started on IV trimethoprim-sulfamethoxazole and steroids 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 (MAC). The infant’s course was complicated by a prolonged pediatric intensive care unit 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, HSV, Cryptococcus, Toxoplasma, and Histoplasma, which were all negative. CMV pneumonitis/viremia was treated with IV ganciclovir and transitioned to PO valganciclovir. He had no evidence of CMV retinitis. Over the hospitalization, HIV viral load declined to 34,700 copies/mL and CD4 count improved to 518 cells/μL (39%). Steroid dosing was tapered. On completion of the 21-day course of treatment, trimethoprim-sulfamethoxazole was given at prophylaxis dosing. He continued on ART and had close follow-up with pediatric HIV specialists, with attainment of viral suppression and healthy clinical status.

Lessons for the Clinician

• 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. PJP is a common initial presentation for perinatally-infected infants, in addition to gastroenteritis, recurrent bacterial infections, and impaired growth.

Suggested Reading

Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States. Department of Health and Human Services. 2023. Available at https://clinicalinfo.hiv.gov/en/guidelines/perinatal. Accessed October 28, 2023.

Panel on Opportunistic Infections in Children with and Exposed to HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Children with and Exposed to HIV. Department of Health and Human Services. 2023. Available at https://clinicalinfo.hiv.gov/en/guidelines/pediatric-opportunistic-infection. Accessed October 28, 2023.

American Academy of Pediatrics. Pneumocystis jirovecii Infections. In: Kimberlin D, Barnett E, Lynfield R, Sawyer M, eds. Red Book: 2021–2024 Report of the Committee on Infectious Diseases. 32nd ed. Itasca, IL. American Academy of Pediatrics. 2021.