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Department of Internal Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumDepartment of Paediatrics, Ghent University Hospital, Ghent, Belgium
CORRESPONDENCE: Eva Van Braeckel, MD, PhD, Department of Respiratory Medicine 7K12E, Ghent University Hospital, Corneel Heymanslaan 10, B-9000 Ghent, Belgium
Department of Internal Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BelgiumDepartment of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
A woman was diagnosed with miliary tuberculosis following a 13th IVF procedure.
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Underlying pelvic TB was suspected, probably the overlooked cause of her infertility.
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Pregnancy and the postpartum are risk factors for a complicated disease course.
Abstract
A woman presented with cough, fever, and dyspnea during a twin pregnancy following a 13th in vitro fertilization procedure. Ultimately, she was diagnosed with miliary tuberculosis and tuberculostatic treatment was initiated, complicated by drug-induced hepatotoxicity. In retrospect, previous pelvic tuberculosis had likely been overlooked. This case report highlights the need to recognize tuberculosis as a cause of infertility even in low-incidence countries and emphasizes that the peripartum period is a major risk factor for drug-induced liver injury.
). Some well-identified risk factors for TB include geographic region, HIV infection, malnutrition, indoor air pollution, type 2 diabetes mellitus, excessive alcohol use, and smoking (
). One of the most severe forms of Mycobacterium tuberculosis infection is miliary tuberculosis, caused by massive lymphohematogenous spread of M. tuberculosis bacilli, which usually occurs in the overtly immunocompromised. Less than 2% of all TB cases in immunocompetent patients are considered miliary infections, although they account for up to 20% of all extrapulmonary TB cases (
A 35-year-old White woman from Belgium, G5P0A4, was admitted in the 15th week of a twin pregnancy because of fever, cough, dyspnea, and weight loss of 5 kg since the beginning of her pregnancy. Her medical history consisted of unspecified infertility, which had been attributed to hyperhomocysteinemia, for which she underwent 13 failed attempts of in vitro fertilization (IVF). The patient was carrying dichorionic diamniotic twins after a new IVF procedure. She had already been treated with amoxicillin-clavulanate 875 mg twice per day in an outpatient setting and was referred to a regional hospital because of persisting complaints.
Physical examination showed the following vital signs: a body temperature of 38.5°C, blood pressure of 108/73 mm Hg, heart rate of 113 beats/min, respiratory rate of 15 breaths/min, and oxygen saturation of 94% at room air. Laboratory results showed a white blood cell count of 6470/µL, elevated liver enzymes (aspartate transaminase [AST]) 188 U/L, alanine transaminase (ALT) 122 U/L, hyponatremia (131 mmol/L), and elevated C-reactive protein (CRP) 109 mg/L. Antibiotic treatment was extended to amoxicillin-clavulanate 1 g thrice per day intravenously (IV), combined with clindamycin 600 mg thrice per day; and soon increased toward piperacillin-tazobactam 4 g 4 times per day IV, combined with 500 mg clarithromycin twice per day because of suspected antibiotic failure. The case was further complicated by premature rupture of membranes at 17 weeks, resulting in anhydramnios. Meanwhile, the patient deteriorated further, necessitating supplemental oxygen administration. A chest X-ray revealed diffuse interstitial markings, justifying an additional low-dose chest computed tomography (CT), which showed a nodular interstitial pattern without clear predisposition for the upper or lower lung fields (Figure 1A). Subsequently, a bronchoscopy with bronchoalveolar lavage for GeneXpert M. tuberculosis and acid-fast staining was performed and autoimmune serology and angiotensin converting enzyme levels were assessed, which all returned negative.
Figure 1A. Computed chest tomography showing pulmonary micronodules associated with miliary tuberculosis. B. Slit lamp examination revealing conjunctival granuloma. C. Liver biopsy with two intralobular epithelioid granulomas, one with a multinucleated Langhans giant cell (black arrow) and one with central caseating necrosis abutting a portal tract (open arrow). D. Placental tissue with large confluent caseous foci with nuclear debris (open arrow). Poorly formed granulomas with multinucleated giant cells can be seen at the junction with preserved villi. E. Ziehl-Neelsen stain on liver biopsy showing an acid-fast bacillus. F. Ziehl-Neelsen stain on placental tissue showing numerous acid-fast bacilli.
Because of persistent respiratory failure and a complicated obstetrical course, the patient was transferred to Ghent University Hospital, where clinical chemistry revealed persistent CRP elevation of 109 mg/L and increasing liver enzyme values with AST 222 U/L, ALT 205 U/L, gamma-glutamyl transferase (GGT) 131 U/L, and alkaline phosphatase (AP) 274 U/L. The decision to perform a liver biopsy was made. The sodium level had also dropped to 125 mmol/L and further workup was compatible with a syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Surprisingly, 2 days later, the GeneXpert was repeated on sputum and the results returned positive, without evidence for rifampin-resistance. Eventually, the pathology report of the liver biopsy revealed findings compatible with tuberculosis (Figure 1C and 1E). Sadly, a spontaneous abortion of the twin pregnancy took place at 21 weeks 1 day gestation and the pathology report of the placenta returned positive for tuberculosis as well (Figure 1D and 1F). Additionally, a nodular lesion was noted in the left eye, compatible with a conjunctival granuloma (Figure 1B). A diagnosis of disseminated M. tuberculosis infection with confirmed pulmonary, hepatic, ocular, and placental involvement was therefore established. In addition, adrenal involvement was suspected because of the refractory SIADH. The patient was promptly started on a 4-drug regimen containing isoniazid, rifampicin, pyrazinamide, and ethambutol, and was discharged 14 days after initiation of antitubercular drugs.
However, the patient was readmitted 2 weeks later because of severely elevated liver enzymes, with AST 837 U/L, ALT 596 U/L, GGT 430 U/L, AP 627 U/L, and bilirubin of 5 mg/dL. Drug-induced hepatitis, most likely secondary to isoniazid or pyrazinamide, was suspected. Given the severity of the tuberculosis, the treatment was immediately and successfully switched to an alternative regimen, consisting of temporary IV amikacin during hospitalization (15 mg/kg), moxifloxacin, rifampicin, and ethambutol, which could eventually be stopped after 12 months.
Additional work up for innate, humoral, or cellular immunodeficiency returned negative. The patient's history was more thoroughly examined and historical reports from a regional hospital were detected, revealing that she had undergone an appendectomy, left-sided salpingectomy, and ovarian cystectomy 16 years earlier. The pathological analysis reported the presence of epithelioid granuloma without caseous necrosis. The patient underwent a laparoscopy 3 years later as a part of the diagnostic process to establish the cause of primary subfertility, which revealed tubal occlusion on the contralateral side and extensive adhesions surrounding both ovaria. She recognized to have been screened through a tuberculin skin test at the age of 18 but had never been treated for latent tuberculosis infection. Taking all this into consideration, it is very likely that pelvic tuberculosis was responsible for the primary infertility and the repeated failure of all the IVF procedures in this patient.
Discussion
This case report highlights different aspects on tuberculosis and women's health, which are often underestimated, particularly in countries with low TB incidence. First, pelvic tuberculosis is considered the second most frequent form of extrapulmonary tuberculosis. It is still a very important cause of tubal infertility, mostly in the developing world, although occurrence in high income countries is not to be underestimated. The fallopian tubes are affected in approximately 90%–100% of the genital tuberculosis cases, whereas the endometrium is involved in 50%–70% of cases, the ovaria in 20%–25% of cases, and the cervix in only 5% of cases (
; Sharma JB et al., 2018). In hindsight, the hyperhomocysteinemia in this patient was likely insufficient to explain her tubal infertility, and the presence of chronic pelvic inflammation should have warranted further workup for tuberculosis.
Second, pregnancy remains an important risk factor for the development of clinical tuberculosis and puts women at risk for a complicated disease course. In case of tubal infertility secondary to genital tuberculosis, IVF is the most successful technique to result in pregnancy. Literature is scarce on the association between IVF and miliary tuberculosis, with the first case reported in 1988 (
). In addition, pregnancy implies a status of relative immune suppression. Disseminated M. tuberculosis infection in immunocompetent patients is thought to be rare. In this patient, after thorough screening for underlying immunodeficiency, only the current twin pregnancy could be withheld as a risk factor. Finally, pregnancy and the 3-month postpartum period pose patients at elevated risk for drug-induced hepatitis, requiring close monitoring of liver function (
In summary, even in low-incidence countries, (1) screening for genital tuberculosis should be considered in women presenting with unexplained tubal infertility and (2) pregnancy and the postpartum period are underestimated risk factors for a complicated TB disease course with an enhanced risk for severe disseminated tuberculosis and tuberculostatic-induced hepatotoxicity.
Conflict of interest: Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Kestens Lore, Van Acker Lander, Hoorens Anne, Kreps Elke O, Haerynck Filomeen, Debrock Alix, Catry Vincent, Weyers Stevens, Roelens Kristien, Van Braeckel Eva.
Funding source
None.
Ethical approval statement
We hereby confirm that we have read and complied with the policy on ethical consent.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors wish to thank the patient for her willingness to share her experience by providing informed consent for this case report and all clinicians involved in the management of this case.
REFERENCES
Addis GM
Anthony GS
Semple PDA
Miller AWF
Miliary tuberculosis in an in-vitro fertilization pregnancy: a case report.
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