Asymptomatic Pulmonary Cryptococcosis And Tuberculosis Co-infection in an immunocompetent Host: A case report.

Pulmonary Cryptococcosis is a rare fungal infection that mostly occurs in immunocompromised host. However, with advancement in diagnostic approach like tissue biopsy, cryptococcal infections are now increasingly being recognised. 1 In immunocompetent host, cryptococcal infection is often asymptomatic and rarely becomes disseminated. 2 Symptom development in immunocompetent host largely depends on burden and virulence of pathogen. Due to similarities in clinical, radiological and pathological findings in Cryptococcosis, Tuberculosis and other fungal infections like Blastomycocosis, it is important to have a tissue biospy to confirm the diagnosis. 3 The aim of this case report is to highlight the investigation necessary to diagnose both fungal infection and Tuberculosis due to similar clinical, radiological features in both. We report a case of Gene Xpert positive Tuberculosis and histopathology proven Pulmonary Cryptococcos in same patient.


INTRODUCTION
Cryptococcus is an encapsulated yeast with more than 30 species distributed in the environment.C. neoformans and C. gatti are the two species commonly known to cause human disease. 5Pulmonary cryptococcosis is a rare fungal infection which remains underdiagnosed due to its highly variable clinical presentation.The clinical presentation can be variable from asymptomatic to fever, weight loss, cough, night sweats and difficulty breathing mimicking tuberculosis. 1diological presentation can be a lobar solitary nodule, multiple nodules in both lungs, pulmonary infiltrates, pleural effusion, hilar lymphadenopathy, lung cavitation. 3In addition, abnormal radiologic findings in cryptococcal disease including nodules, pulmonary infiltrates, pleural effusions, hilar lymphadenopathy, lung cavitation and osteolytic lesions are also found in Tuberculosis. 5rly and correct diagnosis of cyryptococcal infection is crucial not only to control pulmonary infection but also to prevent dissemination.Tissue biopsy for histopathology plays an important role in definitive diagnosis. 6Direct microscopy using India Ink, Giemsa stain, PAS (Periodic Acid Schiff) stain helps distinguish different fungal infection. 6

CASE REPORT
A 65 years old male, non-smoker, diabetic having stable glycemic control with no history of avian exposure or tuberculosis or contact presented in our OPD with complains of fever, dry cough and weight loss for last 8 months.During this period (april-dec 2022) thorough evaluation for Pulmonary Tuberculosis in another tertiary centre was negative including Gene Xpert in BAL.
As shown in figure 3 CT chest, lung window shows bilateral nodular opacities involving apicoposterior and inferior segment in left upper lobe and apical, posterior in right upper lobe.Work up for vasculitis and connective tissue disease including ANCA(Anti-Neutrophil Cytoplasmic Antibody), anti-GBM Ab (Anti-glomerular basement membrane antibody) was negative.Viral serology for HIV, Hepatitis B and C was negative.RA (Rheumatoid factor) and Antinuclear antibody test were negative.
Even after a comprehensive evaluation including a bronchoscopy done for bronchoalveolar lavage(BAL) the results remained inconclusive so, a repeat BAL was planned in our centre.Report was negative for malignant cells and AFB stain was negative for tuberculosis.Sputum work-up for fungal c/s and KOH was also negative.However, BAL for Gene Xpertwas awaited.
CT guided biopsy was also done after 2 days of admission.Biopsy report showed necrosis and scattered multinucleated giant cells with ill formed granuloma.Numerous intracellular and extracellular variable sized yeast with narrow angle budding were noted as shown in Figure 1-4.Fungal infection consistent with Pulmonary Cryptococcosis was reported.However AFB stain came out to be negative.BAL done in our centre showed Gene Xpert positive for Mycobacterium Tuberculosis.
Anti tuberculous medication was started along with antifungal (Tab Fluconazole 400mg OD) planned to be continued for 6 months and 12 months respectively.
During 2 weeks follow up patient had significant improvement in fever and dry cough.

DISCUSSION
Our patient presented with a chronic cough, fever, and weight loss.Multiple, bilateral nodular densities on chest radiography led to a transbronchial biopsy, which showed innumerable, encapsulated, yeast which led to the confirmation of pulmonary cryptococcosis.Along with Gene X-pert testing positive for Tuberculosis.The clinical presentation along with laboratory findings were consistent for diagnosing a concurrent infection of TB with Cryptococci.
Human to human transmission in not reported.Found abundantly in the droppings of pigeons and other birds, 7 Cryptococcus infection predominantly occurs in immune compromised hosted.However with advancement in diagnostic approach like tissue biopsy, infection in immune competent host is being recognised. 1 Concurrent infection of Cryptococcosis and Tuberculosis is rarely reported.Co-infection delays diagnosis leading to increased mortality and morbidity in limited resource settings. 4The similarities in clinical, radiological and pathological findings makes it even more difficult for early diagnosis.Tissue diagnosis is the definitive step in such case.
Radiological presentation may vary from solitary pulmonary nodule, bilateral random distribution of nodule to pulmonary infiltrates.
Advanced non-culture-based diagnostic tests such as galactomannan, beta D glucan, Cryptococcal antigen testing and PCR should be considered during work up for Tuberculosis keeping Fungal infection as an alternative diagnosis. 8finitive diagnosis can be made from tissue biopsy for histopathology.Direct microscopy using India Ink, Giemsa stain, PAS stain can identify Cryptococcosis.
This Co-infection of Cryptoccosis with Tuberculosis has been an overlooked overtime and needs to be considered by both clinicians and microbiologists while managing a patient.
Infectious Diseases Society of America(IDSA) guidelines for treatment of Pulmonary Cryptococcosis in immunocompetent mild to moderate disease includes Tab Fluconazole 400-800mg orally daily for 6-12 months.In severe immunocompromised host induction with Liposomal Amphotericin 3mg/kg/day intravenous or conventional Amphoterecin 0.7-1.0mg/kg plus flucytosine 100mg/kg/day orally 2-4 weeks.Followed by Fluconazole 400-800mg orally daily maintenance for 12 months. 9

CONCLUSION
The aim of this case report is to focus on simultaneous investigation for fungal infection in patients presumed to have Tuberculosis especially in endemic areas.The clinical, NEPALESE RESPIRATORY JOURNAL radiological and pathological similarities in presentation can be tricky hence tissue biopsy helps in definitive diagnosis.

Fig 2 :
Fig 2: CXR after 4 months of starting treatment showing improvement in bilateral opacities.