Dr. K.J.Priyadarshini Gandhi Medical College Invasive Pulmonary Aspergillosis[IPA] as presenting manifestation of CKD Dr. K.J.Priyadarshini Gandhi Medical College

Case Details… 24 year old Mr.X Driver by occupation Non diabetic, denovo detected hypertensive Chronic smoker and occasional alcoholic Dry cough since 45 days Shortness of breath since 10 days Fever since 2 days

Examination… Conscious/coherent Pallor present/No icterus/cyanosis/lymphadenopathy/pedal edema. PR=120/min ;Peripheral pulses felt. BP=Right UL:190/90 mm Hg. Left LL BP=160/80mm Hg RR=24/min,Thoracoabdominal CVS:Apex 7th ICS lateral to MCL. Resp System:B/L basal fine crepitations. P/A and CNS :NAD. Fundus:B/L Papilledema;Grade IV hypertensive retinopathy

Investigations… CBP:8.7/9800/1.7L.PS:NC/HC CUE:Alb3+;RBC 10-15/hpf;Pus cells 3-4 24 hr Urine protein:1.2gm LFT:WNL;S.Albumin:2.5mg/dl S.creatinine:6.6mg/dl S.Na/K/Cl:135/5.6/102 USG abdomen :B/L normal sized kidneys.Grade 2 RPD Serology:HIV/HBSAG/HCV NR

ECG:S/O LVH CXR PA VIEW:B/L patchy consolidation. HRCT chest:B/L reticulonodular opacities involving mid and lower lobes. 2DECHO:Conc.LVH with EF 64%

Summary… Patient presented with pulmonary features and renal involvement Pulmonary : dry cough & Bilateral patchy consolidation Renal : hypertension,Severe renal insufficiency, active urine sediment

Differential diagnosis???

Hospital Course… Initiated on HD through Right IJV. Serum C3 and C4 levels : normal. ANA profile, c- ANCA , p- ANCA, APLA(IgM,IgG,IgA) : negative. Underwent 10 sessions of HD.Creatinine stabilized at 4.6mg/dl. Renal biopsy done.

Hospital Course… Renal biopsy was suggestive of sclerosed glomeruli and IFTA of 80%. Respiratory complaints subsided after 1 week of admission but opacities on chest x ray were persistent. HRCT chest was suggestive of ? Acute pulmonary edema v/s Diffuse alveolar hemorrhage. Patient was subjected to BAL in which Galactomannan for Aspergillus was positive, KOH, Gram stain, Gene Xpert were negative. Patient was started on Tab Voriconazole 200mg bid as a part of treatment for invasive pulmonary aspergillosis.

BAL 4/2/17 Bronchoscopy findings Normal Gramstain Shows polymorphs but no organism Bronchial wash culture Culture shows growth of normal flora AFB (Auramine and rhodamine fluorescent stain) Neg AFB ( ZN stain) GENEXPERT for MTB Not detected KOH No fungal elements Aspergillus Galactomannan(ELISA) Positive (index value > 0.5 – positive) Cytology RBC 40/micL, Negative for malignancy

5 days of voriconazole 2 weeks of voriconazole

Final Diagnosis:IPA as a presenting manifestation CKD stage 5 D

Discussion… Pulmonary disease is caused mainly by Aspergillus fumigatus and has a spectrum of clinical syndromes

IPA… First described in 1953 . Incidence increased in recent past. Mortality rate of IPA exceeds 50% in neutropenic patients and reaches 90% in haematopoietic stem-cell transplantation (HSCT) recipients.

Clinical features Pulmonary Fever unresponsive to antibiotics Cough Sputum production Dysnoea Pleuritic chest pain (d/t infarcts) hemoptysis Symptoms are usually nonspecific

Diagnosis… Histopathology – gold standard Tissue obtained from thoracoscopy or open lung biopsy Septate acute angle hyphae or culture positive for aspergillosis are diagnostic In neutropenic patients, IPA is characterised by scanty inflammation, extensive coagulation necrosis associated with hyphal angio-invasion, and high fungal burden

Diagnosis… In patients with allogeneic HSCT and GVHD, there is intense inflammation with neutrophilic infiltration, minimal coagulation necrosis and low fungal burden. Sputum Immunocompromised 80-90% PPV Immunocompetent <5% PPV. Blood cultures:

Diagnosis… Chest radiography Little use in the early stages of disease because the incidence of nonspecific changes is high. Usual findings include rounded densities, pleural-based infiltrates suggestive of pulmonary infarctions, and cavitations. Pleural effusions are uncommon

Diagnosis… HRCT chest Early diagnosis. ill-defined nodules (67%), Ground glass appearance (56%), Consolidation (44%) Halo sign, which is mainly seen in neutropenic patients early in the course of infection (usually in the first week) and appears as a zone of low attenuation due to haemorrhage surrounding the pulmonary nodule. Air crescent sign, which appears as a crescent-shaped lucency in the region of the original nodule secondary to necrosis

Diagnosis… BAL Diffuse lung involvement. The sensitivity and specificity of a positive result of BAL fluid are about 50% and 97%, respectively. Galactomannan detection in BAL fluid performed significantly better in diagnosing IPA than its detection in serum or BAL fungal stain and culture

Diagnosis… Galactomannan (GM) antigen, 1,3-β-glucan detection in the serum . GM is a major Aspergillus cell-wall component that is released during the growth phase of the fungus, and detection of GM would be indicative for invasive disease. Sensitivity of 71% and Specificity of 89% for proven cases of IPA. The negative predictive value was 92–98% and the positive predictive value was 25–62%. Limitations.

Aspergillus DNA PCR in BAL fluid and serum. The sensitivity and specificity of PCR of BAL fluid samples are estimated to be 67–100% and 55–95%, respectively , while for serum samples the sensitivity and specificity have been reported as 100% and 65–92%, respectively PCR is often associated with false-positive results, because it does not discriminate between colonisation and infection.

Treatment… Echinocandins. The treatment is often prolonged, lasting several months to .1 yr. Prerequisites for discontinuing treatment include clinical and radiographic resolution, microbiological clearance and reversal of immunosuppression.

Take home message… IPA may be an underestimated opportunistic fungal infection not only in critically ill patients, but also in immunocompromised patients and carries a high mortality rate . Presence of a persistent pulmonary infection despite BSA or abnormal thoracic imaging by CT scanning together with one of these risk factors should trigger further diagnostic exploration by collecting respiratory secretions and/or laboratory markers.

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