OPPORTUNISTIC INFECTIONS

Opportunistic infections (OIs) are defined as quot;infections with unusual frequency, microbial etiology or natural course, in a host with impaired normal defence mechanismsquot;.

Incidence of these infections has substantially increased in recent years due to better survival of immuno- compromizsed patients, increasing use of invasive devi­ces, implants, transplants and use of immunosuppressive therapy, etc., along with better diagnostic facilities.

OIs may manifest as: (a) recurrent infections by common organisms, or (b) single or recurrent infections by pathogens, normally considered as non-pathogenic, or (c) unusual course or treatment resistance of a common infection.

Recurrent infections are otherwise also common in early childhood due to environmental factors, and all cases of recurrent infections do not indicate impaired host­defence.

Predisposing factors: Normal host-defence mechanisms include many physical or immunological barriers against infections. Any congenital or acquired disease or environmental factor that impairs one or more of these barriers may cause OIs (Table 8.3). Thus, all OIs do not necessarily mean immunosuppressive state and many of them are due to impaired anatomical or physiological barriers.

Microbial etiology: Any organism is a potential patho­gen in immunocompromised host. Common microbial profile of OIs includes infections due to:

• Low virulence organisms from normal human flora, e.g. coagulase negative staphylococci, enterococci, etc.

• Organisms generally considered as non-pathogenic in normal settings, e.g. Pneumocystis jiroveci, Candida, etc.

TABLE 8.3: Predisposing factors for opportunistic/recurrent infections

a. Impaired skin/mucosal barriers

- Congenital dermal sinuses and tracts

- Acquired: Burns, trauma and surgery

- Foreign body:

#9830; Catheters: Vascular, urinary, dialysis catheter

#9830; Implants: VP shunts, cardiac/orthopedic devices

- ? Vitamin A deficiency

b.

- Mucus drainage: Cystic fibrosis, undrained cavity

- Ciliary function: Post-viral, Immotile cilia syndrome

c. Altered normal flora

- Prolonged/partial antibiotic therapy

d. Congenital immunodeficiency states

- Phagocytic disorders

- B- or T-cell defects

- Complement deficiency

- Impaired local immunity: IgA deficiency

e. Acquired immunodeficiency states

- Severe malnutrition

- Post-infective: Measles, pertussis

- HIV/AIDS

- Disease: Malignancy, sickle cell disease

- Iatrogenic: Transplants, drugs*, splenectomy *For example, anti-malignancy drugs, antibiotics, steroids.

• Organisms prevalent in local hospital setting, e.g. Pseudomonas, Klebsiella, etc.

• Polymicrobial infections, and

• Multi-drug resistant infections.

Clinical spectrum of OIs depends on the primary etiology, site of infection, causative pathogen and extent of immunosuppression. However, some general characteristics are as follows:

• Fever is a sensitive, specific and often the only sign of OIs. Contrary to general view, febrile response is rarely masked, even in severe immunocompromised states.

• Other signs of infection or inflammation, e.g. erythema, exudation, etc. may be minimum or absent in immunocompromised host. These cases may have severe pneumonia with normal X-ray, meningitis with normal CSF and cellulitis without swelling.

• Frequency and severity of OIs directly correlates with severity indicators of immunosuppression, e.g. neutrophil counts (lt;500 mm³) or CD4 counts.

• OIs are usually generalized or multi-systemic, except tissue-tropic infections, e.g. P. jiroveci pneumonia or Cryptosporidium diarrhea.

• Serological tests, e.g. antibody titers or skin tests, e.g. tuberculin test, are unreliable in these cases and negative tests do not exclude corresponding infection.

Some important OIs are as follows:

A. OIs due to impaired physical barriers: Skin and mucus membranes are not only the physical barriers but also offer mechanical (mucociliary clearance), chemical (bacteriostatic fatty acids in skin), enzymatic (lactoferrin, lysozyme secreted by mucus membranes), immunological (secretory IgA in mucus membranes) and microbial (normal colonizing flora) protection against infections.

• Burns patients are susceptible for OIs due to broken skin/ mucosal barriers, presence of necrotic tissue and altered normal flora following antimicrobial therapy or vascular catheterizations. Most of these infections are caused by nosocomial or human flora pathogens, e.g. Pseudomonas, Staph. aureus or CONS and present with severe septicemia or pneumonia.

• Surgical infections are at specific risk for anaerobic infections, due to migration of normal colonizing flora at wound-sites.

• Dermal sinus tracts are usually colonized or infected by Staph. epidermidis or diphtheroids.

B. Device-related infections: Indwelling vascular/ other catheters, shunts and implants act as nidus for localization of infection or the infection may be intro­duced at the time of insertion.

• Vascular catheter-related infections are more common with central than peripheral lines, risk being directly proportional to the duration of cannulation. Over half of them are caused by Staph. epidermidis, followed by gram-negative bacilli and Candida. Frequent change of catheters and catheter site is essential to prevent these infections. Diagnosis is based on identical growth on blood and catheter-tip culture.

• CSF shunt infections are predominantly caused by Staph. epidermidis (gt;70%) and present with: (a) shunt colonization, (b) shunt infection with wound infection/ dehiscence, (c) shunt infection with ventriculitis, and

(d) shunt infection with peritonitis. Shunt removal is often necessary, followed by antibiotics. Vancomycin is the drug of choice for shunt infections.

• Urinary catheter-related infections are common with indwelling catheters, usually caused by gram -ve bacilli or enterococci. These cases present with persistent bacteriuria or symptomatic urinary tract infections. Catheter removal alone is sufficient for asymptomatic bacteriuria, while antibiotics are necessary in symptomatic cases.

• Peritoneal dialysis catheter-related infections are usually due to Staph. epidermidis or aureus and present with local exit-tunnel infection or peritonitis. Vancomycin with a third generation cephalosporin or aminoglycoside is the drug of choice in these cases.

• Orthopedic or cardiac valvular implants are usually infected by CONS or Staph. aureus, presenting as wound infection or endocarditis, respectively.

• OIs due to nebulization/ventilator therapy usually present with pneumonia due to Pseudomonas, Serratia or Iegionella.

C. Acquired immunodeficiency states may be due to the disease, (e.g. PEM, HIV, malignancy) or iatrogenic (steroid/cytotoxic therapy, splenectomy, bone marrow transplants).

• Severely malnourished children are prone for gram­negative septicemia as well as severe disease with common infections, e.g. measles, varicella and tuber­culosis, due to impaired T cell function, phagocytic activity and complement activity.

• Post-infective transient immunosuppression for 2-3 months is common after measles and pertussis infection, which may lead to reactivation of underlying tuberculosis.

• Transplanted individuals are highly susceptible for OIs due to immunosuppressive drug/radiation therapy, prolonged invasive devices, surgical injury, and graft versus host disease (GVHD). The type of OIs in these cases depends on time-course of transplant—bacterial infections in pre-operative preparatory phase, anaerobic infections in peri-operative period, and viral (CMV, RSV) or PCP infections in post-operative period. While septicemia and pneumonia is common in marrow transplants, children with renal/liver transplant are additionally susceptible for urinary tract infections and cholangitis, respectively.

• Malignancy is a common cause of OIs due to primary or iatrogenic immunosuppression as well as nosocomial infections. Microbial profile in these cases varies according to absolute neutrophil counts, as follows:

- Non-neutropenic cases: Viral and fungal infections, PCP and toxoplasmosis.

- Neutropenic cases: Serious bacterial infections due to gram +ve cocci, e.g. Staph. aureus, CONS, enterococci, etc. or gram-negative bacilli, e.g. Pseudomonas, Klebsiella, etc.

Note that meningitis is unusual in granulocytopenic patients.

D. Inherited immunodeficiency disorders are rare (Ch 8.2), but should be suspected in cases with warning signals (Table 8.2), without an acquired cause for impaired host-defence.

Diagnostic evaluation of suspected OI aims to confirm the microbial etiology as well as to identify the predis­posing factors and includes:

• History, including: (a) review of medical records to confirm the frequency and nature of recurrent infections, (b) family history of similar illnesses, TB/ HIV or consanguinity (for inherited defects), (c) past history of immunosuppressive infections, e.g. measles, pertussis, etc. (d) treatment history of prolonged steroid/cytotoxic therapy or splenectomy, and (e) epidemiological history for environmental causes for recurrent infections.

• Pattern of infections may provide important clues to the nature of immunodeficiency, as follows:

- Recurrent bacterial infections indicate probable B-cell defects.

- Atypical course of mycobacterial, viral, fungal or intracellular infections, e.g. toxoplasmosis indicate probable T-cell defects.

- Recurrent staphylococcal or gram-ve infections, as well as mucocutaneous infections indicate probable defects in phagocytosis, which are also characterized by inadequate pus production.

- Recurrent infections due to capsular organisms, e.g. Pneumococci, H. influenzae or Salmonella indicate splenic dysfunction or complement deficiency.

• Co-existing illnesses are important diagnostic clues for secondary immunodeficiency disorders (malignancies, malnutrition, sickle cell disease, nephritic syndrome) as well as inherited immunodeficiency disorders (Table 8.4).

• Laboratory evaluation in these cases includes baseline screening tests for common defects and search for microbial etiology, followed by more selective investigations, guided by clinical suspicion (Table 8.5).

Management depends on the identified cause, though some broad principles in management of immuno­compromised children include:

• Avoidance of unnecessary microbial exposure, e.g. overcrowding.

• Avoidance of live vaccines in severe cases.

CVID: Common variable immunodeficiency

TABLE 8.5: Laboratory investigations in OIs

Step I: Base line screening tests:

• Hematological:

- Leukocyte count¹

- Leukocyte morphology²

- Platelet count³

- Howell-Jolly bodies⁴

- ESR for chronic infection, TB

• Radiological: Chest, sinuses, mastoid, etc.

• Microbiological cultures from suspected sites

• Immunological tests: Serology, TT (unreliable)

• Relevant tests for predisposing illness

Step II: Specific immunological screening tests:

• Suspected B-cell defects

- S. IgA, IgG and IgM levels⁵

- S. IgG subclass measurements

- Isohemagglutinin (anti-A and B) titers⁶

- Vaccine-antibody titers (tetanus, diphtheria)⁷

- B-cell count

• Suspected T-cell defects (Only if ALC is low)

- T-subpopulation count (by flow cytometry)

Absolute CD4 count

CD4/CD8 ratio (N: gt;4:1)

NK cell counts

- T-cell function tests

In vivo: Tuberculin, candida skin tests

In vitro: Lymphokines assay

• Suspected phagocytic defect

- Nitroblue tetrazolium dye test (NBT)

- Leukocyte function tests

• Suspected complement deficiency

- CH₅₀ activity with control

- Direct C₃-C₄ immunoassays

Step III: Molecular tests (inherited defect)

- Index case

- Prenatal diagnosis

¹Neutropenia, T-cell defects, eosinophilia in hyper IgE syndrome ²Abnormal in Chediak-Higashi syndrome

³Thrombocytopenia in Wiskott-Aldrich syndrome

⁴In splenic dysfunction or asplenia

⁵Hypergamaglobulinemia indicates HIV or CGDC;

⁶Indicative of IgM function

⁷Indicative of IgG function

• Prophylactic vaccinations for capsular organisms, e.g. pneumococci, meningococci, H. influenzae, etc.

• Prophylactic or early antimicrobial therapy.

• Adequate drainage of infection site, e.g. abscess, empyema, etc.

• Replacement therapy with plasma (complement deficiency) or IV immunoglobulins in select cases.

• Specific therapy or bone marrow transplantation (T-cell defects), interferon, etc.

8.4