# A Perplexing Case Highlighting the Diagnostic Conundrum of Miliary Tuberculosis Mimicking Sarcoidosis and Progressing Into Hemophagocytic Lymphohistiocytosis

## TL;DR

A patient with symptoms resembling sarcoidosis and later hemophagocytic lymphohistiocytosis was ultimately diagnosed with miliary tuberculosis, highlighting diagnostic challenges and the need for early treatment.

## Contribution

This case emphasizes the diagnostic limitations of TB testing and the importance of early empirical anti-TB therapy in high-probability miliary TB cases.

## Key findings

- Miliary TB can mimic sarcoidosis and progress to HLH, leading to diagnostic delays.
- TB testing may yield false negatives despite strong clinical suspicion, necessitating empirical treatment.
- Delayed diagnosis and treatment of miliary TB can result in fatal outcomes despite confirmatory testing.

## Abstract

Establishing the diagnosis of miliary tuberculosis (TB) can be challenging due to the heterogeneous clinical presentations and low sensitivity of diagnostic tests. Miliary TB shares overlapping clinical, radiological, and histopathological features with other chronic granulomatous diseases, such as sarcoidosis, often posing a significant diagnostic challenge for clinicians. A 36-year-old male from Haiti presented with a four-month history of recurrent fever, dry cough, night sweats, and weight loss. Chest imaging revealed innumerable widespread miliary nodules throughout the lungs bilaterally, raising a high clinical suspicion for miliary TB. The work-up for bacterial, fungal, and viral infection was negative, and there was no evidence of malignancy. Surprisingly, extensive TB testing yielded negative results. The interferon-gamma release assay (QuantiFERON TB Gold Plus®), Mycobacterium tuberculosis (MTB) complex polymerase chain reaction (PCR), and repetitive sputum cultures for acid-fast bacilli (AFB) were all negative. A lung biopsy was performed due to an unexpectedly negative tuberculosis work-up and revealed non-necrotizing granulomatous inflammation, with no AFB identified on bronchoalveolar lavage (BAL) or histopathological staining.

Additionally, the next-generation sequencing technique was conducted using microbial cell-free DNA and was negative for tuberculosis or any other pathogen. Therefore, sarcoidosis was considered the most likely diagnosis based on the exclusion of infectious etiologies. The patient was started on high-dose steroids. However, the patient failed to respond clinically and developed worsening transaminitis, uptrending ferritin, and pancytopenia. His H-score was as high as 256 points, which suggested the probability of hemophagocytic lymphohistiocytosis (HLH) was as high as 99%. A bone marrow biopsy revealed multiple small foci of noncaseating granulomatous inflammation with hemophagocytic cells. The patient was started on etoposide steroids and empiric broad-spectrum antibiotics. Despite aggressive management, the patient’s condition rapidly deteriorated as he developed acute hypoxic respiratory failure requiring mechanical ventilation, refractory shock, and multi-organ failure.

The infection screen was repeated due to the worsening clinical status. To everybody’s surprise, the repeated next-generation sequencing on hospital day 26 detected MTB complex. This was confirmed with positive AFB staining, MTB complex PCR, and AFB cultures on BAL samples. A four-drug anti-TB regimen was promptly commenced. However, the patient's condition continued to deteriorate rapidly, and the patient expired one week later. This complex case raised several diagnostic and therapeutic dilemmas. First of all, the optimal treatment approach remains unclear, considering the risk of infection secondary to immunosuppressants for HLH might outweigh the benefits. It also highlights the diagnostic limitations of TB testing and the overreliance on diagnostic tests that should be avoided, especially when there is a high pretest probability of miliary TB. Early initiation of empirical anti-TB therapy should be considered to improve outcomes, considering the mortality of miliary TB is extremely high.