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Sir, Clofazimine is a lipophilic phenazine antibiotic and exhibits antimycobacterial and anti-inflammatory properties. It is primarily utilized for the therapeutic management of leprosy and drug-resistant tuberculosis.1 Clofazimine has received approval from the World Health Organization (WHO) and the National Tuberculosis Elimination Program (NTEP) for the treatment of drug-resistant tuberculosis. A significant proportion of patients worldwide who have multidrug-resistant tuberculosis (MDR-TB) are prescribed this medication. We would like to present a case in which bronchoalveolar lavage (BAL) of a treated MDR-TB patient revealed the presence of macrophages containing clofazimine crystals. A 30-year-old male patient, previously diagnosed as MDR-TB, presented at the outpatient department with left pleural effusion and underlying collapse consolidation. The patient was a diagnosed case of sputum-positive MDR-TB in 2021 and completed 24 months of treatment in April 2023, that is, three months after completion of treatment. The patient exhibited symptomatic improvement with a weight gain of 5 kg. Given the past history of MDR-TB, the decision was made to perform a bronchoscopy so as to obtain BAL fluid for mycobacterial culture and drug sensitivity testing. During the bronchoscopy procedure, it was noted that the patient's BAL fluid and washings had a purplish tinge. So further analyses were conducted. Following centrifugation, a dark purple sediment was observed in the BAL fluid Figure 1. Microscopic examination of the BAL fluid, using a Neubauer hemocytometer, revealed the presence of black-to-red, needle-shaped crystals within alveolar macrophages Figure 2. Bronchial wash gene Xpert and mycobacterium growth indicator tube (liquid media for tuberculosis culture) (MGIT) culture were negative.Figure 1: Light microscopy of bronchoalveolar fluid- Clofazimine crystals seen within macrophages high resolution and clofazimine laden macrophages seen on low resolutionFigure 2: Brochoalveolar lavage- Purple reddish BAL seen immediately after collection. After few minutes sediment is formedClofazimine is a lipophilic antimicrobial agent belonging to the riminophenazine group. It is known for its distinctive bright-red colour, which can cause long-lasting skin and bodily fluid discoloration.1 It is widely recognized and endorsed by WHO and NTEP as an antitubercular drug for the treatment of MDR-TB in patients. Clofazimine is given in both extended oral and shorter MDR-TB regimens. For leprosy management, clofazimine is used in combination with other drugs, such as dapsone. Clofazimine exerts a slow bactericidal effect on Mycobacterium primarily through its action cell membrane. It may influence the bacterial respiratory chain and ion transporters to some extent. Furthermore, anti-inflammatory properties suppress the activity of T-lymphocytes. Despite its long residence time in the body, it still necessitates daily administration.2 Clofazimine exhibits a high degree of lipophilicity, resulting in its preferential deposition within adipose tissues and the reticuloendothelial system. Within these locations, macrophages uptake the drug, distributing it throughout the body. Crystalline deposits of clofazimine have been observed in various anatomical sites, like mesenteric lymph nodes, adrenal glands, subcutaneous fat, liver, bile, gall bladder, spleen, intestine, muscles, bones and skin.2 A portion of an orally ingested dose of clofazimine can be detected in the faeces, potentially indicating excretion via the bile, while traces are eliminated through sputum, sebum and sweat. The excretion of unchanged clofazimine and its metabolites in urine is minimal.2 In patients receiving clofazimine, 75–100% of them develop skin, conjunctivae and bodily fluid discolouration ranging from orange-pink to brownish-black. Skin discolouration may persist for months to even years after stopping therapy.3 In rare instances, a condition known as clofazimine storage enteropathy may occur. Histologically, this is characterized by the expansion of the lamina propria due to the presence of crystal-laden macrophages. Clofazimine has been associated with instances of abdominal obstruction, which can, in some cases, be fatal. Therefore, any complaints of abdominal pain, nausea or vomiting should be promptly investigated, and if clofazimine is identified as the cause, doses should be reduced or discontinued accordingly.4 There are only two case reports documenting the presence of clofazimine crystals in BAL fluid. Silverman et al.5 described a case in which this drug was being used to treat Mycobacterium avium–intracellulare complex infection in patients with acquired immunodeficiency syndrome (AIDS). The appearance of these clofazimine crystals in the macrophages obtained from BAL resembled the negative images seen in mycobacterial infections, displaying a pseudogaucher appearance of the cells. Another report by Divate and Sharma6 provided a detailed description of the characteristic cytological features associated with clofazimine-induced crystal-storing histiocytosis. This was observed through polarizing microscopy in frozen sections, unstained wet preparations and stained smears. Notably, the stained smears revealed faint, linear spaces within alveolar macrophages, which may suggest the dissolution of crystals. We conclude that the presence of clofazimine crystals within alveolar macrophages in BAL fluid provides valuable insight of the distribution and accumulation of this drug. While previous reports have detailed clofazimine crystals in other tissues, the findings within pulmonary macrophages are noteworthy. Overall, this case letter sheds light on the unique properties and distribution of clofazimine within the human body and the importance of further research to better understand its clinical implications. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Thorve et al. (Fri,) studied this question.