Infectious Complications of HIV Infection

Opportunistic infections (OIs) were key to the identification of the AIDS and have been a major cause of HIV-associated morbidity and mortality. An unusual clustering of cases of Pneumocystis jirovecii pneumonia ( Pneumocystis pneumonia, PCP) in the early 1980s led in part to the recognition of AIDS. Other AIDS-associated OIs, including disseminated mycobacterial disease, cryptococcal meningitis, cerebral toxoplasmosis, and cytomegalovirus (CMV) retinitis, were recognized soon thereafter.

In the mid-1990s, improved treatment and prevention strategies and the introduction of combination antiretroviral therapy (ART) dramatically reduced the incidence of OIs and the mortality rate for HIV. Between 1994 and 2000, the overall mortality rate for children with HIV in the US decreased from 7.2 to 0.8 deaths per 100 person-years. Likewise, the incidence of most OIs fell dramatically ( Table 112.1 ). ^, Despite these advances, OIs continue to occur, and optimized outcomes depend on their early identification, effective treatment, and prevention. ^, Essential reference include Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-infected Adults and Adolescents and Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children , which are updated regularly ( clinicalinfo.hiv.gov ).

TABLE 112.1

Incidence of Infections per 100 Patient-Years Among Children Living With HIV Before and After the Advent of Combination Antiretroviral Therapy

Condition	Before cART ^, (prior to 1996)	After cART ^, ^, ^, (after 1996)
OPPORTUNISTIC INFECTIONS
Pneumocystis jirovecii pneumonia	1.3–5.8	0.09–0.3
Nontuberculous mycobacterial infection	1.3–1.8	0.15–0.2
Cytomegalovirus disease	0.7–1.5	0.03–0.1
Toxoplasmosis	0.06	NA
Progressive multifocal leukoencephalopathy	0.06	NA
Cryptosporidiosis	0.3–0.6	0–0.03
Other Infections
Otitis media and sinusitis	72	2.9-3.5
Bloodstream infection	3.3	0.35
Bacterial pneumonia	11.1	1.2–2.2
Bacterial meningitis	0.1	0.05
Varicella	4.7	0.44
Herpes zoster	2.9	0.76–1.1
Candidiasis, esophageal or pulmonary	1.2–1.4	0.04–0.44
Urinary tract infection	1.6	0.35
Tuberculosis	0.4	<0.5

cART, combination antiretroviral therapy; NA, not available.

Advances in ART have led to a dramatic reduction in the rate of mother-to-child transmission and much-improved survival for children who acquire HIV. At present, most persons living with perinatal HIV in the US are between 18 and 30 years of age. However, globally, large numbers of children continue to be born to women with HIV. Most of these HIV-exposed children are HIV-uninfected and have a much lower risk of OIs than children living with HIV. However, these HIV-exposed but uninfected children have immunologic derangements, resulting in increased susceptibility to childhood illnesses, including diarrhea, pneumonia, and sepsis.

Pathogenesis

Healthy neonates are at risk for serious infection because of the immaturity of several components of their immune system, including B and T lymphocytes, phagocytes, and complement. The naïvety of the developing immune system likely contributes to the rapid HIV disease progression as well as to frequent complicating infections in infants and children with perinatally acquired HIV.

HIV infection of the fetus or neonate has a profound effect on cellular immunity. Destruction of the thymus gland is observed in spontaneous abortuses from mothers with HIV. Surprisingly, depletion of CD4 ⁺ lymphocytes is rarely recognized at the time of birth. However, as early as 1 or 2 months of age, infants with HIV have a significant depletion in CD4 ⁺ lymphocyte counts. Suppression of cell-mediated immunity is largely responsible for increased susceptibility to PCP and opportunistic mycobacterial, fungal, and viral infections.

Despite having hypergammaglobulinemia, most children with symptomatic HIV infection have humoral immune dysfunction that predisposes them to recurrent bacterial infections. Humoral deficiency results from dysregulation of T-lymphocyte–mediated responses and polyclonal stimulation of B lymphocytes by poorly controlled infectious agents. In vitro lymphoproliferative responses to B-lymphocyte mitogens and specific antigens often are poor. In vivo, there is impaired specific antibody production after immunization with T-lymphocyte–independent antigens (e.g., capsular polysaccharide of Streptococcus pneumoniae ) and T-lymphocyte–dependent antigens, particularly in those not receiving ART or with a low CD4 ⁺ count. Primary humoral immune responses and recall responses (i.e., amplification and immunoglobulin class switch) are defective in children with HIV infection.

Phagocytic function also can be altered by HIV infection. Neutropenia and defects in neutrophil chemotaxis and bactericidal activity have been described. ^, Neutrophil superoxide production can be depressed in children with advanced HIV disease. ^, This combination of phagocyte abnormalities compromises the ability of persons with HIV to kill bacterial and fungal pathogens. Although the precise pathogenesis of these abnormalities is unknown, studies suggest that neutropenia and neutrophil dysfunction are partly mediated by abnormal regulation by cytokines (e.g., granulocyte colony-stimulating factor [G-CSF]). Recombinant G-CSF administration in adults with HIV has reversed neutropenia and corrected neutrophil-killing defects.

Immune Reconstitution Inflammatory Syndrome

A child with advanced immunosuppression who initiates or restarts ART can have a rapid improvement in immune competence, reflected by an increased CD4 ⁺ lymphocyte count. In the face of an underlying infection, the resulting inflammatory response can result in the unmasking or worsening of symptoms, known as the immune reconstitution inflammatory syndrome (IRIS).

In children, IRIS most often occurs with mycobacterial infections (i.e., Mycobacterium avium complex [MAC], M. tuberculosis, and the Bacille Calmette-Guérin [BCG] vaccine), varicella-zoster virus (VZV), herpes simplex virus (HSV), and cryptococcal infections but can be seen with PCP, CMV, hepatitis B and C virus, Toxoplasma , and JC virus infection (i.e., progressive multifocal leukoencephalopathy [PML]). ^, IRIS usually occurs within the first 2–3 months after initiating effective ART and is associated with virologic suppression and a rapid rise in the CD4 ⁺ lymphocyte count. IRIS should not be interpreted as a failure of ART.

To avoid IRIS, children should be evaluated carefully for underlying occult infections before initiating ART. The optimal time to start ART in a child with an active OI differs by pathogen and site(s) of infection and consultation with an experienced HIV care provider is recommended. For OIs without effective therapy (e.g., PML, Kaposi sarcoma), ART should be initiated promptly because immune reconstitution may resolve the infection. For some OIs with effective therapy (e.g., PCP, hepatitis B and C virus infection, cryptosporidiosis, and microsporidiosis), ART should be started within 2 weeks of initiating treatment of the OI or when the patient is clinically stable. However, for selected OIs (pulmonary and extrapulmonary tuberculosis including meningitis, MAC disease, disseminated cryptococcal disease including meningitis, and CMV retinitis), IRIS can cause severe end-organ disease and ART should be delayed until after starting OI treatment. If symptoms of IRIS develop after ART, the OI should be treated, ART usually is continued, and anti-inflammatory therapy is considered.

Epidemiology and Etiologic Agents

In children, as in adults, untreated HIV infection is characterized by an increased frequency of a specific group of serious OIs. In addition, an increased frequency of childhood infections of a less serious nature also contributes to the overall morbidity of the disease. The frequency of the different infections among children with HIV in the years preceding combination ART varied by age, pathogen, and immunologic status. The most common infections among children living with HIV in the US included serious bacterial infections (SBIs) such as pneumonia and bloodstream infection (BSI), PCP, nontuberculous mycobacterial infections, and CMV disease ( Table 112.1 ). ^, ^, Despite a dramatic decrease in the rate of OIs among patients receiving ART, ^, ^, the types of infections that occur have not changed. ^,

Table 112.1 compares the incidence of infections in children before and after the use of ART. Before ART and the use of P. jirovecii prophylaxis in early infancy, 7%–20% of infants with HIV developed PCP, making it the most common AIDS-defining OI in children ( Table 112.2 ). More than 50% of cases occurred between 3 and 6 months of age. A low age-adjusted CD4 ⁺ lymphocyte count or percentage was the major determinant of risk. Although PCP still is observed in infants and children with HIV, the incidence has decreased dramatically in the US with the use of prophylaxis and early initiation of ART.

TABLE 112.2

Common AIDS-Defining Infections in Children <13 Years of Age Before the Combination Antiretroviral Therapy Era

From Centers of Disease Control and Prevention. Personal communication, 2011.

AIDS-Defining Infection	Proportion of Children (%)
Pneumocystis jirovecii pneumonia	35
Lymphoid interstitial pneumonitis	23
Recurrent bacterial infections	21
Esophageal or pulmonary candidiasis	21
Cytomegalovirus disease	11
Mycobacterium avium complex infection	9
Severe herpes simplex infection	5
Cryptosporidiosis	5

AIDS, acquired immunodeficiency syndrome.

Oral candidiasis occurs in 15%–40% of children with HIV infection and is more common among children with low CD4 ⁺ lymphocyte counts or symptomatic HIV disease. ^, Whereas oral candidiasis is common at all stages of HIV disease, esophageal and pulmonary candidiasis are far less common and typically restricted to patients with advanced HIV disease. Esophageal and pulmonary candidiasis accounted for approximately 17% and 4%, respectively, of AIDS-defining illnesses in children before ART.

SBIs (e.g., BSI, pneumonia, sinusitis, meningitis, osteomyelitis, pyogenic arthritis, mastoiditis, abscess of an internal organ) were reported in 40%–60% of children with HIV before ART, with an overall incidence of 44 cases per 100 patient-years of follow-up. Recurrent bacterial infections represent an AIDS-defining condition and accounted for 21% of all pediatric AIDS-defining illnesses reported to the Centers for Disease Control and Prevention (CDC) through 2007 ( Table 112.2 ). Minor infections (e.g., otitis media, urinary tract infection, infections of the skin or soft tissue) were threefold more common than serious infections. The use of ART has resulted in a dramatic drop in the incidence of SBIs, but rates remain higher than those in HIV-uninfected children ( Table 112.1 ). ^,

The incidence of SBIs among children with HIV is highest in children <1 year of age and those with advanced immunosuppression evidenced by low CD4 ⁺ lymphocyte counts. In one study of children with HIV, 25% had their first SBI by 6 months and 37% by 12 months of age; BSI, pneumonia, and urinary tract infections were the most commonly seen infections.

S. pneumoniae has been the single most common cause of SBIs in children with HIV. ^, ^, In a study of those <36 months of age, pneumococcal BSI occurred with an annualized rate of 11.3 episodes per 100 patient-years ; this rate is more than threefold that observed for children with sickle cell anemia and 12-fold that reported in one study of adults with AIDS. Other bacteria causing SBIs include Salmonella species, Staphylococcus aureus, and Neisseria meningitidis .

Although CMV infection is common, disseminated disease, chorioretinitis, and colitis caused by CMV are uncommon in children. The role of CMV as a cause of pneumonia in children with HIV is controversial; CMV usually is associated with another pulmonary opportunistic pathogen (often P. jirovecii ) . HSV commonly causes infection of the oral or genital mucous membranes that is more severe and prolonged than would be expected ; esophageal or pulmonary disease occurs rarely. CMV disease, cryptosporidiosis, and disseminated MAC ^, occur predominantly in children with advanced HIV disease and severely depressed CD4 ⁺ lymphocyte counts. Without prophylaxis, up to 20% of children with HIV and CD4 ⁺ lymphocyte counts <50 cells/μL develop disseminated MAC infection.

Although data are currently limited and rapidly evolving, the disease course of SARS-CoV-2 infection in persons with HIV does not appear to differ greatly from that in persons without HIV, after accounting for other co-morbidities. However, additional caution for those with advanced immunosuppression or poorly controlled HIV is warranted.

Approach to Suspected Infection in a Child Living With HIV

Fever

Fever is a common reason for unscheduled outpatient clinic visits and hospital admissions for children with HIV. Clinical manifestations and diagnostic considerations for these children are as diverse as those of uninfected children. Although most children with HIV with acute febrile illnesses have mild, self-limited illnesses presumably caused by a viral infection, they are at increased risk for more serious illnesses ( Box 112.1 ). Differentiation can be difficult.

BOX 112.1

Causes of Fever Without an Obvious Source in Children Living With HIV

Common causes (e.g., respiratory viruses, urinary tract pathogens)
Bacteremia
Focal bacterial infection (e.g., sinusitis, pneumonia, organ abscess)
Catheter infection
Salmonellosis
Tuberculous or nontuberculous mycobacterial infection
Fungal infection (e.g., candidal esophagitis, cryptococcal meningitis, pneumonia)
Pneumocystis jirovecii infection
Toxoplasmosis
Cytomegalovirus infection
Epstein-Barr virus infection
Herpes simplex virus infection
Hepatitis
Esophagitis
Lymphoma and other types of malignancy
Drug fever

Febrile children with HIV require a thorough medical history and physical examination. The character and duration of symptoms, HIV disease status (including the most recent CD4 ⁺ lymphocyte count), adherence to ART and OI prophylaxis when applicable, and history of recent travel and exposures, including sick contacts, are important. A careful search for evidence of focal infection or inflammation and an assessment of the severity of illness (i.e., toxicity) should be performed. Clinical features of focal infection in children with HIV are similar to those observed in immunologically healthy children, with fever and local signs of inflammation often found. BSI should be suspected in an acutely ill child including those with a focal infection such as pneumonia, cellulitis, or osteomyelitis.

The approach to the acutely febrile child with HIV without localizing signs is challenging. Not all patients require diagnostic testing or antibiotic therapy, although both should be considered, especially for those with high fever (>39.4°C) or advanced HIV disease. The likelihood of an OI, such as disseminated MAC, Cryptococcus neoformans, or CMV enteritis or retinitis, typically increases as the patient’s CD4 ⁺ lymphocyte count decreases.

The white blood cell count, often used as a screening test for SBI in immunologically normal children, must be interpreted in the context of the patient’s baseline values. Neutropenia commonly results from trimethoprim-sulfamethoxazole (TMP-SMX) use and can result from HIV infection and the use of other medications. Other diagnostic studies can include radiographs of the lungs and sinuses; culture of blood for bacteria, mycobacteria, and fungi; culture of the urine; culture or testing by molecular methods of throat or nasopharyngeal specimens and blood for viruses (including CMV); cryptococcal and other fungal antigen tests; Epstein–Barr virus serologic tests; hepatic enzyme measurements; and ophthalmologic examination for chorioretinitis. Examination of cerebrospinal fluid (CSF) may be indicated to determine cell counts; protein and glucose concentrations; nucleic acid testing and/or culture for bacteria and mycobacteria, fungi, viruses, and Toxoplasma gondii; cryptococcal antigen testing; and cytologic evaluation.

Empiric antibiotic therapy for children who have mild or asymptomatic HIV infection who have an acute febrile illness should be similar to that used in the treatment of immunologically normal children with comparable clinical manifestations. While oral antibiotic therapy is appropriate in most cases, children with more advanced HIV disease may require broader spectrum parenteral antibiotics.

The selection of antibiotic agents for expectant therapy is influenced by factors such as the likely source of infection (e.g., community-acquired vs. healthcare-associated infection), presence of a central venous catheter, immunization status, use of prophylactic antibiotics, and CD4 ⁺ count. Empiric antibiotic therapy should be directed against a limited number of likely pathogens. Unless convincing clinical or laboratory evidence exists for serious opportunistic fungal, mycobacterial, or viral infection, therapy usually is directed against likely bacterial pathogens.

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