INFECTIOUS MONONUCLEOSIS

TABLE 10.41: Complications of infectious mononucleosis

• Splenic rupture

• Respiratory: Pneumonia, obstruction (? adenoids)

• Neurological:

- Aseptic meningitis,

- Acute cerebellar ataxia

- Guillain-Barre syndrome

- Alice in wonderland syndrome[‡‡‡]

• Hematological[§§§] [****]: Anemia, thrombocytopenia

*autoimmune or due to bone marrow depression

**loss of perceptual capabilities

Diagnosis must be suspected in a clinical triad of prolonged fever, pharyngitis and generalized lymphadenopathy, supported by:

• Lymphocytosis with atypical lymphocytes (larger lymphocytes with eccentric, large, indented nucleus and lower nuclear-cytoplasm ratio).

• Paul-Bunnell-Davidsohn test, for presence of nonspecific heterophile IgM antibodies with titers lt;1:28 taken as positive. A rapid qualitative slide test (mono-spot) based on similar principles is available to detect EBV infection in gt;50-90% cases.

• Specific EBV antibodies tests, anti-VCA (viral capsid antigen) or anti-EA (early antigen) antibodies detect early infection, while anti-EB nuclear antigen anti­bodies are positive in convalescent phase or due to previous infection.

• Viral culture from oropharynx is positive for ~ 1 year after primary infection or during intermittent shedding.

Treatment is non-specific, including supportive measures like bed rest, antipyretics and avoidance of splenic trauma.

Steroids (PO prednisolone 1 mg/kg/d ? 2 weeks) are indicated only in complicated cases with - (i) severe airway obstruction, (ii) symptomatic thrombocytopenia, (iii) autoimmune hemolytic anemia, and (iv) aseptic meningitis.

High doses of acyclovir with/ without steroids reduce viral shedding but do not affect the severity or course.

Prognosis is excellent with complete recovery in 4-8 weeks in absence of acute complications and recurrence in unknown. Rare case may develop chronic active EBV infection with progressive immunodeficiency and often succumb to opportunistic infections, hemophagocytosis, multiorgan failure, or EBV-positive lymphomas. Stem cell transplantation is the only option in cases of chronic active EBV infection with complications.

Prevention involves avoidance of contact with an infected case and no vaccine is available at present. Contact sports should be avoided to prevent splenic rupture.

Note: EBV was the first virus found to be associated with malignancies and has been implicated in:

• Benign lymphoproliferative illnesses, e.g. hemo-phagocytic syndrome, oral hairy leukoplakia and lymphocytic interstitial pneumonitis (LIP) in AIDS.

• Malignancies, e.g. Burkitt's lymphoma, Hodgkin disease, nasopharyngeal carcinoma, leiomyosarcoma.

Epidemiology: Children usually contract infection from a household contact (75-90%), rarely from other in schools, child-care centers or health-care settings. Infected children, even if asymptomatic, have higher nasopharyngeal viral loads than adults and shed the virus for a longer period.

Pathogenesis: SARS-CoV-2 is transmitted as droplet infection or by contaminated fomites and surfaces. On entry, virus gets attached to angiotensin converting enzyme-2 (ACE₂) receptors present on the ciliated respiratory epithelium and gastrointestinal mucosa. After local replication, viremia develops followed by development of either appropriate immune response to clear the virus or dysregulated immune response with development of cytokine storm - responsible for clinical deterioration with acute respiratory distress syndrome (ARDS), multi-organ failure and sometimes, death. It is also characterized by elevation of inflammatory markers, e.g. CRP, procalcitonin, interleukin (IL6/10) and D-dimer levels, also leading to increased thrombosis.

Children usually have milder disease, due to: (a) immaturity of ACE₂ receptors, (b) relatively immature immune system, unable to mount intense inflammatory response and cytokine storm. However, children lt;1 year or with underlying medical conditions, e.g. obesity, immunocompromised states, chronic lung/heart disease, diabetes or other metabolic diseases are at higher risk of severe disease.

Clinically, while ~15-20% cases are asymptomatic, rest present after an incubation period of ~4-6 days with fever, upper respiratory infection, myalgia, diarrhea and vomiting as initial symptoms. Further course may be classified as follows:

• Mild cases, presenting as uncomplicated upper respiratory infection with fever, sore throat, rhinorrhea, cough and breathlessness, which usually recover in

1- 2 weeks.

• Moderated cases progressing to non-severe pneumonia with tachypnea but without severe hypoxia or danger signs and SpO₂ ranging between 90-94% in room air.

• Severe COVID cases develop severe pneumonia with danger signs, e.g. inability to breastfeed or drink, grunt­ing, severe lower chest in drawings, cyanosis, lethargy, somnolence, or organ dysfunction with ARDS, septic shock, coma and/or seizures and MODS.

Diagnosis: RT-PCR test to detect presence of SARS- CoV-2 nucleic acid from nose and throat swab is the gold standard for diagnosis, though the sensitivity varies from 60-70%. Rapid antigen test may be used in symptomatic cases (only) with sensitivity of 40-50%, if RT-PCR is not available. HRCT of the chest is not recommended for

diagnosis in children. However, Chest X-ray is required in cases with lower respiratory symptoms to exclude other cases.

Moderate to severe cases with COVID-19 need moni­toring for inflammatory markers, e.g. CRP, procalcitonin, interleukin (IL₆), TNF -#945;, D-dimer assay, etc.

Mild cases can be managed at home with symptomatic treatment with paracetamol and adequate feeds/fluids, without antibiotics or antiviral drugs. Parents should be counseled about COVID-appropriate behavior, watch for danger signs and report in cases of worsening.

Moderate cases with non-severe pneumonia must be hospitalized with:

• Oxygen therapy with nasal cannula (lt;4 L/min) or face mask (lt;6 L/min) to maintain SpO₂ as 94-98%.

• Supportive therapy to ensure adequate nutrition as well as fluid and electrolyte balance.

• Antibiotics, only if there is a strong suspicion of bacterial infection

• Steroids, only if rapid deterioration and gt;5 days have passed since onset of disease.

• Monitoring for deterioration of clinical status (respi­ratory distress, hypotension) and SpO₂,

• Communication with parents to alleviating anxiety and ensure COVID-appropriate behavior.

Severe cases with severe pneumonia and danger signs or organ dysfunction must be transferred to intensive care unit for continuous monitoring and managed with:

• Oxygen therapy with targeted saturation of 94-98%, using high-flow nasal cannula or HFNC (2 L/kg/min) or non-rebreathing mask or NRBM (10-15 L/min) to provide ~100% FiO₂.

• Ventilatory support using low tidal volume (4-8 ml/ kg) with optimum positive end-expiratory pressure (PEEP) to keep P plateau lt;28 cm H₂O and driving pressure lt;15 cm H₂O. Use of cuffed endotracheal (ET) tube, in-line suction with minimal disconnection of ventilator circuits and early-proning should be considered in children with severe ARDS.

• Supportive therapy to ensure adequate nutrition as well as fluid and electrolyte balance. Children with shock must be managed with isotonic crystalloid boluses, inotropes and hydrocortisone (IV 2-4 mg/ kg/24 hours) for catecholamine-resistant cases, if they are not on steroids. Fluid restriction may be needed in cases with ARDS/MODS.

• Empiric antibiotics, as per the hospital policy after collection of blood cultures.

• Steroids if gt;5 days have lapsed since the onset of symptoms with a increasing oxygen demand on HFNC, NRBM, non-invasive ventilation, invasive ventilation, or extracorporeal membrane oxygenation with Dexamethasone 0.15 mg/kg (maximum 6 mg) or Methylprednisolone 0.75 mg/kg OD (maximum 30 mg) for 5-7 days.

• Antivirals, e.g. Remdesivir: are not recommend in children but may be considered in hospitalized cases with emergent/increasing need for supplemental oxygen and: (a) age 16 years, (b) age 12 years with presence of the high-risk factors for severe disease, and, (c) age lt; 12 years in consultation with pediatric infectious disease specialist. A 3-5 day course of remdesivir (IV 5 mg/kg, to maximum 200 mg over 30-120 min followed by 2.5 mg/kg to maximum 100 mg daily single dose for 3-5 days) early in the disease has shown up to 87% reduction in deaths. There is no role for remdesivir beyond 10 days of infection, and can cause hepatic derangement.

• Prophylactic anticoagulation is not routinely recom­mended except in hospitalized children with: (a) strong personal/ family history of venous thromboembolism, (b) indwelling central venous line with additional risk factors, (c) D-dimer gt;5 times of upper limit, and

(d) children alread y on anticoagulation therapy. Low molecular weight heparin may be used as SC 0.5 mg/kg twice daily till discharge, provided there is no renal dysfunction cases with confirmed thrombosis need therapeutic anticoagulants, i.e. low molecular weight heparin as SC 1 mg/kg twice daily for ~12 weeks.

• Transfusions is indicated in children with lt; 7 g/dl with stable oxygenation and hemodynamics or lt;10 g/dl for those with refractory hypoxemia or shock.

• Intensive monitoring is needed in all cases for vital signs, inflammatory markers, blood gases and coagulation profile.

Management of the Newborn of COVID-19 Infected Mothers

All COVID positive deliveries should be conducted preferably in dedicated centers with standard infection containment protocols. IAP recommends that:

• Neonatal resuscitation should follow standard guide­lines, using appropriate COVID-protective measures. Risk of postnatal infection in the baby may be reduced if mothers wear a triple-layer mask and adheres to respiratory etiquettes.

• Mother-infant dyads should be roomed-in and exclu­sive breastfeeding should be encouraged, regardless of maternal COVID-19 status.

• Kangaroo care is recommended for low birth weight neonates, regardless of the COVID-19 status of the mother or neonate.

• Symptomatic/neonates should be isolated with mother in a designated area, segregating suspect and confirmed cases.

• All forms of respiratory support are at risk of gene­rating aerosols and HCWs must wear appropriate PPE, preferably in a negative air pressure area.

• Baby should be tested as follows:

- Within 24-48 hours, if mother tested positive within

14 days before or 2 days after delivery. However rooming-in should not be delayed. Repeat testing is advised in asymptomatic newborns before discharge to prevent further transmission.

- Within 5^ih-7^ih day, if mother or a family member/ HCW dealing with baby is exposed to a COVID positive case,

- Immediately in all symptomatic neonates, which may be repeated after 24-48 hours, if first report is negative despite strong suspicion.

• Neonates with asymptomatic or mild disease require no additional laboratory tests and stable mother/baby dyad may be discharged after 24-48 hours but must be followed-up for 14-28 days.

• All moderate to severe cases must be investigated and managed as per regular protocols with full infection control measures.

Multisystem Inflammatory Syndrome in Children (MIS-C)

MIS-C, also termed as pediatric inflammatory multi­system syndrome (PIMS), is a rare but life-threatening complication of COVID-19 infection in children, characterized by hyperinflammatory syndrome with involvement of multiple organs, usually seen after

2- 6 weeks of acute infection.

Diagnosis of MIS-C depends on fulfillment of all six parameters included in WHO diagnostic criteria 2020 (Table 10.42).

Investigation depends upon severity of disease and include:

• Tier-1 screening in all cases on admission including - CBC, CRP, ESR, liver and renal function tests, blood sugar, blood gas analysis, and SARS-CoV-2 serology/ RT-PCR. Tier-one screen is considered as positive if both of these criteria are fulfilled:

- CRP gt; 5 mg/dl and/or ESR gt; 40 mm/hour

- At least one of these: Absolute lymphocyte count (ALC) lt; 1,000/pl, platelet count lt; 150,000/pl, Na lt; 135 mEq/L, neutrophilia, and hypoalbuminemia

• Tier-2 tests are required in cases positive on tier-one screening and include: ECG, echocardiogram, B-type natriuretic peptide (BNP), troponin-T, ferritin, lactate dehydrogenase, procalcitonin, interleukin 6 (IL-6), prothrombin time, activated partial thromboplastin time, D-dimer, and fibrinogen.

TABLE 10.42: WHO criteria for MIS-C (All Six)

• Age 0-19 years

• Fever gt; 3 days

• Clinical signs (any two)

- Rash, bilateral non-purulent conjunctivitis, or mucocuta­neous inflammation signs (mouth, hands or feet)

- Hypotension or shock, cardiac dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocar­diographic findings or elevated troponin/BNP)

- Evidence of coagulopathy (prolonged PT/PTT, elevated D-dimer)

- Acute gastrointestinal symptoms (diarrhea, vomiting, or abdominal pain)

• Elevated markers of inflammation e.g. ESR, CRP or procalci­tonin

• No other obvious microbial cause of inflammation, inclu­ding bacterial sepsis, toxic shock syndromes or tropical infectious diseases, i.e., malaria, dengue etc.

• Evidence of COVID-19 infection: positive RT-PCR/RAT or

Serology or contact with an individual with COVID-19

(BNP: B-type natriuretic peptide; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; PT: Prothrombin time; PTT: Partial thromboplastin time; RAT: Rapid antigen test)

A child is considered to have MIS-C only if: (a) both, Tier 1 and 2 tests are positive, and (b) other causes or tropical infections have been excluded. Isolated elevated COVID-19 antibodies are not synonymous with MIS-C.

Management: For management, MIS-C may be classified into four categories:

1. MIS-C without shock;

2. MIS-C with shock (tachycardia, hypotension, requiring fluid bolus 30 ml/kg, or inotropic support) or MODS with two or more organ involvement;

3. MIS-C with Kawasaki phenotype, meeting complete/ incomplete Kawasaki disease criteria (Table 24.11);

4. MIS-C with refractory disease, not responded to first- tier therapy with IVIG and low-dose steroids within 48 hours.

Important components of management include:

(a) stabilization in terms of ventilation and perfusion,

(b) treatment of organ dysfunction, (c) anti-inflammatory therapy, (d) monitoring for disease progression, and

(e) long-term follow-up for complications.

• Anti-inflammatory therapy to reduce tissue inflam­mation or prevent progression of myocardial dys­function usually includes: IVIG (2 gm/kg maximum 100 gm) infusion over 8-12 hours along with low- dose IV Methylprednisolone (2 mg/kg/day), slowly switching to PO prednisolone and tapered over 2-3 weeks. While only Methylprednisolone (without IVIG) is enough in cases without shock, oral low-dose Aspirin (PO 3-55 mg/kg/day) must be added in those with Kawasaki phenotype.

In children with refractory MIS-C despite above treatment, IV/SC Anakinra (gt;4 mg/kg/day) can be

used after expert consultation. Infliximab/tocilizumab are not recommended in children.

• Anticoagulation: MIS-C with documented thrombosis, ejection fraction lt; 35%, coronary artery Z score #8805; 10 or giant aneurysm with diameter gt; 8 mm need anticoagulation with low molecular weight heparin SC 1 mg/kg/dose (0.75 mg/kg/dose in lt;2 months) for 2 weeks after discharge. Low-dose aspirin (PO 3-5 mg/kg/day; max 80 mg/day) should be used if platelets gt;80,000/pl and continued till normal coronary arteries are confirmed at 4 weeks after diagnosis.

Outcome: Mortality rate is 1-2%, higher in cases with delayed diagnosis/ treatment. Late complications include coronary artery aneurysm (25%), cardiac dysfunction, renal involvement and systemic thrombosis.

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