CME INDIA Case Presentation by Dr Nishith Kumar, Pulmonologist, Ranchi.

CME INDIA Case Study

How Presented?

• A 57yr/Male k/c/o Bronchial Asthma, Post Tubercular Bronchiectasis/ Covid 19 Pneumonia was shifted to non Covid ICU after testing negative.
• Serum Procalcitonin – WNL. 

HRCT Thorax

The following test was done

• Galactomannan- Aspergillus Antigen(ELISA) Test.
• Work up like sputum/tracheal aspirate fungal Culture is still awaited.

What to suspect?

• COVID-Associated Pulmonary Aspergillosis (CAPA).
• Aspergillosis in patients with severe COVID-19 is not an uncommon entity especially in patients with pre-existing immunocompromising conditions or structural lung abnormalities.
• As the patient was on prolonged immunosuppressive therapy CAPA was suspected.
• It’s important that patient may present with nonspecific radiological features like pulmonary infiltrates, consolidation, and nodules.
• Classical Radiologic features such as halo sign, air-crescent sign, or cavitation are rare. So, a high index of suspicion is key to early diagnosis.

How treated?

• First-line options for CAPA/Invasive Pulmonary Aspergillosis is IV voriconazole (loading dose 6 mg/kg body weight twice a day on day 1 followed by 4 mg/kg body weight twice a day, Day 2 onwards).

Post Covid Scenario

• One patient is intubated & on ventilator right now. He had past H/O post tubercular bronchiectasis & Bronchial Asthma. He’s with us since last 20-25 days & have been shifted to non Covid ICU about a week back.
• Another patient is 33 yr./Male with no known co morbidities. He presented with Haemoptysis in OPD. He tested negative on 25th May, Recovered at home. Never took corticosteroid. But yes, he was taking thrice daily steam inhalation since last few months.
• Another one also around 37 yrs. admitted in non Covid ICU. He was previously admitted elsewhere & had received high dose of steroid > 1 month.
• COVID is now emerged as very important risk for IA.
• Previously, IPA was recognized as occurring mainly in patients with neutrophil deficiencies. Such patients generally have serious immunosuppressive conditions, such as malignant hematopathy, solid organ or hematopoietic stem cell transplants, and human immunodeficiency virus (HIV) infection, or are receiving long-term immunosuppressive therapy .However, it has increasingly been found that nonneutropenic patients, especially those with chronic obstructive pulmonary disease (COPD), bronchiectasis, or previous tuberculosis, are also prone to pulmonary Aspergillus infections.

Dr H K Jha, MD, CMO, CGHS, Ranchi says:

• Covid-19 patient with pneumonia usually have impair immune system due to disease itself, long steroid use (3 to 4 weeks), long immobility, poor nutrition, oxygen dependency, and long ICU stay. The possibilities of fungal infections are high. Incidence is much Increased, with pre-existing medical conditions.
• IPA occurs in both neutropenic and non-neutropenic patients.
• We suspect IPA in Covid-19 pneumonia patients when worsening clinical symptoms such as: 
  • Persistent and raising temperature in spite of antibiotics.
  • Recrudescent fever after a period of effervescence of at least 48 hrs.
  • Increasing dyspnoea.
  • Increasing CRP.
  • Worsening PaO2/ Fio2 ratio.
  • Haemoptysis.

D/D
-Bacterial pneumonia

• Mucormycosis
• Pulmonary embolism
• Simple non invasive pulmonary Aspergilloma .
• Reactivation of old tuberculosis
  — GPA
  -Non Covid 19 viral pneumonia
  -Lung abscess
  -Eosinophilic pneumonia
  -Aspiration pneumonia

• We do direct microscopy, cytology, C/ S, Galactomannan test, CT chest.
• Galactomannan test has high sensitivity and specificity in patient with IPA with neutropenia but in non-neutropenic patients its sensibility is decreased due to Neutrophils digest cell wall of fungus (Asp f).Specificity is not decreased
• CT chest usually have Halo sign, Air crescent sign, cavities.
• I think, serial weekly sample of GM may require in all patients in ICU with worsening symptoms.

CME INDIA Learning Points

• Invasive aspergillosis (IA) is a severe infection
• It occurs in patients with prolonged neutropenia, following transplantation or in conjunction with aggressive immunosuppressive regimens (e.g., prolonged corticosteroid usage, chemotherapy). IA has an extremely high mortality rate of 50% to 80% due in part to the rapid progression of the infection (i.e., 1-2 weeks from onset to death).
• Approximately 30% of cases remain undiagnosed and untreated at death.
• A serologic assay was approved by the FDA for the detection of galactomannan( a molecule found in the cell wall of Aspergillus species).
• Serum galactomannan can often be detected a mean of 7 to 14 days before other diagnostic clues become apparent.
• It is worth to mention that monitoring of galactomannan can potentially allow initiation of presumptive antifungal therapy before life-threatening infection occurs.
• Definitive diagnosis of IA requires histopathological evidence of deep-tissue invasion or a positive culture.
• Remember that  histopathological evidence is often difficult to obtain due to the critically ill nature of the patient and the fact that severe thrombocytopenia often precludes the use of invasive procedures to obtain a quality specimen.
• The sensitivity of Fungal culture in this setting also is low, reportedly ranging from 30% to 60% for bronchoalveolar lavage fluid.
• Thus, the diagnosis is often based on nonspecific clinical symptoms (unexplained fever, cough, chest pain, dyspnoea) in conjunction with radiologic evidence (computed tomography: CT scan).
• The definitive diagnosis is often not established before fungal proliferation becomes overwhelming and refractory to therapy.

CME INDIA Tail Piece

What is Galactomannan?

• Galactomannan (GM) is a polysaccharide antigen that exists primarily in the cell walls of Aspergillus species. GM may be released into the blood and other body fluids even in the early stages of Aspergillus invasion, and the presence of this antigen can be sustained for 1 to 8 weeks. (Therefore, detection of the GM antigen level via enzyme-linked immunosorbent assay (ELISA) can be useful in making an early diagnosis of IPA.

How to interpretate the Galactomannan Test?

• A positive result supports a diagnosis of invasive aspergillosis (IA). Positive results should be considered in conjunction with other diagnostic procedures, such as microbiologic culture, histological examination of biopsy specimens, and radiographic evidence.
• A negative result does not rule out the diagnosis of IA. Repeat testing is recommended if the result is negative but IA is suspected. Patients at risk of IA should have a baseline serum tested and should be monitored twice a week for increasing galactomannan antigen levels.

What are False Positivity conditions?

• False positive Aspergillus Galactomannan test have been found in patients on intravenous treatment with some antibiotics or fluids containing gluconate or citric acid such as some transfusion platelets, parenteral nutrition or PlasmaLyte.

Is this test useful in monitoring?

• Galactomannan antigen levels may be useful in the assessment of therapeutic response. Antigen levels decline in response to antimicrobial therapy.

Reference:

(1) Thompson GR, Patterson TF: Aspergillus species. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020:3103-3116

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