Abstract
The accurate diagnosis of pathologies with obscure presentations requires comprehensive clinical evaluation, epidemiological context, and consideration of the patient’s clinical or hospital course. In this case report, we describe a 30-year-old female receiving antituberculosis therapy who developed multiple signs and symptoms that were unexplained by any single diagnosis, including multiple rashes with different features. The patient was determined to have drug induced lupus with concomitant HIV infection. Physicians should consider the possibility of co-existing disease processes when a single unifying diagnosis that reconciles all aspects of the patient’s presentation cannot be identified.
Introduction
Drug-induced lupus (DIL) is an autoimmune reaction to medication that typically manifests as a milder syndrome resembling systemic lupus erythematosus (SLE). 1 Drugs known to be associated with DIL include isoniazid, procainamide, hydralazine, anti-TNF therapies, chemotherapeutic drugs, and a myriad of other pharmacologic agents. 2 Pakistan is a low-middle income country (LMIC) that bears an immense burden of infectious diseases. These include tuberculosis (TB), which is endemic and has an annual prevalence and incidence of up to 348/100 000 and 276/100 000, respectively,3,4 in addition to an increasing number of HIV-AIDS cases. 5 As such, physicians might more regularly encounter patients with active tuberculosis whose immunocompromised state may be part of the onset of AIDS-associated opportunistic infections. Conversely, given the variety of ways in which TB may present clinically and its relatively high prevalence in our setting, physicians may be too quick to diagnose and treat patients for it without sufficient evidence or consideration of alternative entities or explanations. In this case-report, we describe a patient who developed a lupus-like presentation after receiving anti-tuberculosis therapy and was then found to be HIV positive. The case illustrates the importance of a comprehensive histor, scrutiny of examination findings, epidemiologic context, awareness of the properties of frequently prescribed drugs, and a systematic approach that attempts to adequately and coherently explain a patient’s clinical picture.
Patient History
The patient was a 30-year-old female. She was a resident of the city of Karachi, where our teaching hospital is located. The lady presented with a protracted history of recurrent upper and lower respiratory tract infections for which she had received numerous unspecified antimicrobial regimens. At the time of presentation, she reported a productive cough with purulent sputum, generalized weakness, anorexia, weight loss, and intermittent fever over the preceding 2 months. The highest documented temperature was 100°F/37.8°C. Furthermore, following the development of weight loss, the patient had more recently been experiencing severe watery diarrhea that had now persisted for more than 3 weeks.
During this time, she visited a physician regarding these symptoms and had been prescribed empiric antituberculosis therapy. Specifically, the patient was asked to take 3 tablets of Myrin-P Forte (each consisting of Isoniazid 75mg, Rifampin 150mg, Ethambutol 275mg, Pyrazinamide 400mg) every morning, in addition to a 50 mg supplement of vitamin B6 (pyridoxine) daily. This was in the absence of testing to confirm active TB. However, she was not fully compliant with treatment.
Finally, 10 days before presenting to our clinic and having initiating anti-mycobacterial therapy, the patient developed arthralgia and rashes on her face, chest, and upper extremities.
The patient reported no prior hospitalizations or significant medical or surgical history with the exception of a blood transfusion received during childbirth.
Clinical Examination
Physical examination of the patient showed a young lady of small stature.
Assessment of vitals found a regular heart rate of 84 beats per minute, with systolic and diastolic blood pressures of 107 and 65 mmHg, respectively. The respiratory rate was found to be 18 breaths per minute. At the time of examination, the patient was afebrile.
A pale, erythematous malar rash sparing the nasolabial fold was present on the patient’s face, with the typical appearance of that seen in lupus, and her scalp showed alopecia. The patient’s anterior and posterior cervical lymph nodes and axillary lymph nodes were palpable bilaterally. Inspection of the chest revealed a linear scarring rash of pustular nature on the right chest anteriorly that was consistent with the typical appearance of shingles. No abnormal cardiac sounds were heard on auscultation of the heart, but crackles were heard in the right lower lung field. Abdominal examination revealed no significant findings except for splenomegaly. Muscle strength was assessed to be 5/5 in all 4 limbs, and no joint deformities or swelling was noted. However, the lady’s calveswere found to be symmetrically wasted in both legs but were non-tender.
Differential Diagnoses and Investigations
Considering its endemicity in our region, the urban environment, and the patients’ history, tuberculosis was considered as a potential component of her illness. This was also clearly the diagnosis made by her previous physician, who had prescribed anti-mycobacterial combination therapy. However, the history and physical was suggestive of a more complex disease process versus a single diagnosis of tuberculosis. The possibility of an immunodeficient state was suspected, including the primary immunodeficiencies of CGD (chronic granulomatous disease) or CVID (common variable immunodeficiency) or secondary immunodeficiency due to HIV-AIDS. The rash on the patient’s chest had the classical appearance of Herpes Zoster and was distinct to that on her face, lending credence to the suspicion of AIDS. A connective tissue disorder or lymphoproliferative malignancy was also considered, given the patient’s newer malar rash and arthralgias. Laboratory tests, imaging studies, lymph node biopsy, and microbiologic investigations were ordered accordingly.
Laboratory Investigations
The initial lab workup was ordered with consideration of the past medical history, clinical context of the patient and the region, along with the examination findings. The relevant findings are detailed in Table 1.
The normal ranges are according to the institution’s reported lab values for adult females.
Follow-Up and Outcomes
The patient was determined to have active HIV infection with a CD4+ counts of were 126 cells/mL (reference range for the normal count: 430-1740 cells/mL). Treatment with a week long course of valacyclovir was initiated to manage the patient’s Herpes Zoster, in addition to starting cotrimoxazole (trimethoprim-sulfamethoxazole) for Pneumocystis and Toxoplasma prophylaxis. Anti-Tuberculosis treatment was not restarted given the negative sputum microbiologic investigation results, which was followed by resolution of the patients other signs and symptoms of what was now identified as DIL. Serum markers for hepatitis B and C viruses were tested due to the patient’s history and the endemicity of these infections in the region and were found to be non-reactive. The patient’s final diagnosis was DIL superimposed upon HIV-AIDS with opportunistic infections.
Discussion
This case illustrates the importance of a thorough history and physical examination by physicians who are cognisant of epidemiological trends in their setting and the properties of commonly prescribed pharmacological agents.
The patient described in this case was initially treated for tuberculosis, which is highly prevalent in Pakistan. 3 Patients are often at an increased risk of active TB infection due to high rates of exposure, malnutrition, 7 and cramped dwellings in Karachi’s poverty-stricken and dank urban environments. As such, it is not uncommon in our setting to see patients immediately started on anti-mycobacterial therapy when presenting with features such as chronic respiratory tract symptoms, weight loss, and fever.
However, our patient had additional findings that were not adequately explained by a diagnosis of tuberculosis, such as the recurrent infections preceding the present complaints, persistent watery diarrhea, and her 2 distinct rashes with evidently separate etiologies – the malar rash on her face and the herpetiform rash on her chest. Furthermore, keen readers will have noted the history of blood transfusion during childbirth. The Pakistani health system struggles with adherence to appropriate protocols during blood product administration, and unsafe practices have been associated with high rates of transmission of infective agents such as HIV 8 and Hepatitis-C. 9 In this context, a methodical approach to thoroughly explain the patient’s state was both warranted and necessary to arrive at the correct diagnosis.
Our case also illustrates the importance of a complete knowledge of potential adverse reactions to drugs that are commonly prescribed. This instance of DIL was attributable to isoniazid, which is frequently prescribed in our setting due to the endemicity of tuberculosis. However, beyond epidemiology, several features of our patient’s history pointed towards isoniazid/medication being responsible for the signs and symptoms of lupus that were observed. Although SLE was a possibility in the patient, given her age and sex, 10 DIL commonly presents with rash and arthralgia but is unlikely to involve the cardiac, renal, or central nervous systems. 1 This parallels our patient’s clinical vignette, where arthralgia, alopecia, and malar rash were noted but no cardiac, renal, or CNS disease was detected during examination or via investigations. Additionally, the abrupt onset of symptoms after initiating therapy for tuberculosis also supported the diagnosis of DIL. The occurence of DIL is thought to be related to factors affecting drug metabolism such as acetylation, and hence affects individuals unpredictably. 11 Pyrazinamide-induced hyperuricemia is also a well-known phenomenon that can lead to arthralgias but the presence of of a malar rash in tandem rendered this an inadequate explanation on its own. 12 A valuable diagnostic test in scenarios where clinical history is inadequate to distinguish between SLE and DIL isthat of anti-histone antibodies. While Anti-nuclear and anti-double strandedDNA antibodies poorly discriminate between the 2 conditions, anti-histone antibodies are commonly positive in DIL, with a sensitivity of up to 95% overall, but are found in only a minority of patients with SLE. 13 However, their diagnostic utility varies across different drugs, testing positive in less than half of cases for agents such as propylthiouracil and minocycline, and may be positive in many cases of idiopathic SLE.
Stronger evidencethat this patient had DIL was the resolution of her lupus-like symptoms on discontinuation of anti-mycobacterial therapy. In settings such as ours, where ordering additional tests may place unsustainable financial burdens on patients, diagnostic information in suspected cases of drug related presentations can be obtained by discontinuing the agent and observing clinical improvement and, in some cases where it may be done safely, restarting the drug and noting a return of the patient’s signs and symptoms.. It is important to note that symptoms of DIL typically disappear within a few weeks after discontinuing the causative drugs, while the associated serum markers may remain positive for several months. 1
In rare cases where a patient with tuberculosis experiences drug-induced lupus, it is important to stop the offending agent and treat the tuberculosis with second-line options such as late-generation fluoroquinolones, bedaquiline, or intravenous amikacin, streptomycin, and carbapenems. Unfortunately, there are no established guidelines for managing such situations.
This case report has certain limitations. Due to the lack of standardized health records, we do not have all details pertaining tothe patient’s initial clinical features at the time of presentation before the anti-tuberculosis treatment was started. Additionally, no lymph node biopsy was performed to minimize financial toxicity as clinical assessment and initial workup was deemed adequate to treat the patient. Follow-up testing, such as for serum complement levels, could not be conducted for these reasons.
Conclusion
The novelty of our case lies in the unique combination of clinical features produced byco-existing multisystem processes, including 1 that was induced by medication. Initially treated for tuberculosis, our patient developed DIL that was superimposed on her HIV-AIDS-associated opportunistic infections. A systematic approach to diagnostic testing that complemented a comprehensive clinical evaluationenabled quick identification of the causes of the patient’s illness and subsequent treatment. Trainees may note that, when dealing with complex cases, application of Occam’s razor in pursuit of a unifying diagnosis often leads to appropriate clinical decision making but it remains crucial to consider the possibility of multiple co-existing disease entities. This is particularly significant when dealing withconditions that are highly prevalent, medications that are recognized for a wide array of adverse effects, or with patients who have recently received an intervention.
