Of the 561 articles identified, 15 were included: 1 randomized clinical trial (RCT) [16], 7 observational studies [11–13, 21–24] and 7 case reports [25–31] (Figure). Tables 1 and 2 detail the lead author, year of publication, country of research, population, and diagnostic error-delay and adverse events.
Table 1
Observational and case report studies related to overdiagnosis
Type of study | Lead author Year Reference | Country | Population | Overdiagnosis |
Observational studies | Haddad E (2019) [11] Haddad E (2019) [12] Itani O (2020) [13] | France France France | 301 patients PTLDS 4 weeks 1000 patients 3 centers Paris, Besançon, Nancy 15 patients 6 months | Overdiagnosis = 80.7% (n = 243) differential diagnosis: psychiatric (depression, post-traumatic stress, burnout syndromes, etc.) 25.2% (n = 76 ) rheumatological (osteoarthritis, scoliosis) 15.9% (n = 48) neurological (Parkinson’s and amyotrophic lateral sclerosis)12.3% (n = 37) OSA 4.9% (n = 15) No diagnosis 6.6% (n = 20) Overdiagnosis: 90.4, 88, 85% differential diagnosis: psychiatric 25, 19 and 13% rheumatological 16, 14 and 32% neurological 12, 6 and 5% no diagnosis 6, 29 and 26% Overdiagnosis: 100% (n = 15) differential diagnosis: psychiatric FSS 60% (n =9) neurological 20% (n =3), 1 OSA |
| Kobayashi Y (2019) [22] | United States | 1261 patients | Overdiagnosis: 84.1% (n = 1061) |
| Peri F (2019) [24] | Italy | 7 children | Overdiagnosis: 100% (n = 7) differential diagnosis: psychiatric (n = 6) viral infection (n = 1- |
Case report | Andany N (2015) [7] | United States | a 35-year-old man with chronic fatigue > 1 year | Public Serology LB < 0 Private Serology > 0 |
| Nelson C (2015) [25] | United States | 3 patients PTLDS ATX treatment (tetracyclines, clarithromycin and hydroxychloroquine) | diagnostic delay pituitary tumor Hodgkin lymphoma stage 4 lung cancer |
| Di Battista ME (2018) [26] | Italy | 61-year-old patient: doxycycline (21 days and 14 days) | diagnostic delay (4 years) frontotemporal dementia |
OSA: Obstructive Sleep Apnea ; ABX: antibiotics ; LB: Lyme borreliosis ; FSS: functional somatic syndrome |
Table 2
RCTs, observational studies and case reports related to adverse events (AEs)
RCT | Krupp LB (2003) [16] | United States | 55 PTLDS patients 28 ceftriaxone IV 27 placebo 6 months | AEs: diarrhea ceftriaxone group 43% placebo group 25% Hospitalizations: 4 ceftriaxone group: 1 anaphylaxis, minor anaphylactic reactions: 2 placebo group: 3 IV catheter sepsis |
Observational studies | Itani O (2020) [13] | France | 15 patients On average 6.8 ABX / 476 days | AEs: 27% (n = 4) 1 clostridium difficile colitis 3 fungal infections |
| Trautmann A (2020) [21] | France | 16 Disulfiram patients | Various and moderate AEs: 81.2% (n = 13) |
| Goodlet KJ (2018) [23] | United States | 3127 patients Group 1: 1102 ABX per os Group 2: 150 IV Groupe 3: 1875 placebo | AEs: group 1: 18.7%, group 2: 16.8%, group 3: 13.4% Infections 20.4%, gastrointestinal disorders 6.2%, electrolyte disorders 2.6% Hospitalizations: group 1: 2.2%, group 2: 7.3%, group 3: 0.9% Emergencies: group 1: 3.4%, group 2: 11.3%, group 3: 1.9% |
Cases report | Johnstone T (2018) [27] | Australia | 41-year-old woman Glutathion + Phosphatidylcholine | AEs: bacterial septicemia then Clostridium Difficile colitis |
| Issacs D (2016) [28] | Australia | 15-year-old woman Hyperthermia and ABX IV | AEs: severe dehydration due to Clostridium Difficile diarrhea |
| Shelton A (2019) [29] | United States | 32-year-old woman ABX IV (rifabutin, metronidazole, ivermectin, and pyrimethamine) then ABX per os (meropenem, clindamycin, tigecycline, and ciprofloxacin) | AEs: Mycobacterium goodii multifocal pneumonia on central venous catheter |
| Marcks CM (2016) [30] | United States | 45-year-old woman ABX 3 months per os (doxycycline, minocycline and trimethoprim-sulfamethoxazole | AEs: DRESS Syndrome |
| De Wilde M (2017) [31] | Belgium | 76-year-old woman ceftriaxone IV | AEs: drug-induced immunohemolytic anemia |
Randomized Clinical Trial: RCT ; intravenous (IV) : antibiotics: ABX |
Overdiagnosis: Attribution of Symptoms to LB
Overdiagnosis has been described in cohort studies and case reports. The results are summarized in Table 1.
Cohort Studies
In France, two observational studies were conducted by Haddad et al. and published in 2019 [11, 12]. Rechallenging the PTLDS led to an overdiagnosis rate of 80.7%. In the second study, the overdiagnosis rate ranged from 85 to 90.4%. The differential diagnoses made were mostly psychiatric, rheumatological and neurological disorders. The categorization of differential diagnoses could be difficult, particularly for disorders with somatic symptoms (e.g. fibromyalgia), which could be classified as psychiatric, rheumatologic, or no diagnosis [12]. Another observational study published in 2020 by Itani et al. included 15 patients with PTLDS for at least six months. The overdiagnosis rate was 100% [13].
In the United States, an observational study conducted by Kobayashi et al. was published in 2019. The overdiagnosis rate was 84.1% [22].
In Italy, Peri et al. analyzed medical records of 7 children with PTLDS. PTLDS had strongly influenced their schooling. A review of the clinical history revealed a 100% overdiagnosis rate [24].
Case Report
In 2015 Nelson et al. reported three cases in the United States of oncologic diagnostic errors and delays due to a diagnosis of PTLDS [25]. The first case was a 30-year-old man who had been suffering with joint pain and memory loss for 12 years. Following the onset of visual field deficit and syncopal episodes, he was diagnosed with a pituitary tumor. Facial morphological sequelae and cardiomyopathy appeared to be attributable to this diagnostic delay. The second case was a 30-year-old man with fatigue, loose stools and abdominal pain for 4 years. The diagnosis of PTLDS was made despite the absence of clinical signs of LB and living in an endemic area. The patient had received several cycles of oral and intravenous antibiotic therapy. Following discontinuation of his treatments, a gastric biopsy of a mesenteric lymph node and a PET scan revealed stage IV Hodgkin's lymphoma. The patient died 2 years later. The third case was a 50-year-old man with asthenia for 2 weeks and an influenza-like illness for 3 days. Doxycycline adapted to early LB was prescribed. Subsequently, an erythematous rash appeared under his left shoulder. Two more courses of doxycycline were performed with partial improvement. A diagnosis of PTLDS was made. Five months after this diagnosis, an infectious disease specialist requested a chest CT since the patient had smoked for 18 years. It confirmed the diagnosis of lung cancer.
In 2016, Di Battista described the case of a 61-year-old Italian woman with cognitive impairment [26]. Four years earlier, a diagnosis of LB had been made on the basis of a typical erythema migrans. In view of cognitive disorders and a major depressive syndrome persisting despite two courses of doxycycline, PTLDS was diagnosed. A PET scan and a brain MRI were performed after one year, due to the loss of autonomy and worsening of the disorders leading to the diagnosis of frontotemporal dementia.
Adverse effects of the drugs used
Adverse events were described in one randomized clinical trial (RCT), observational studies and case reports.
RCT and observational studies
In 2003, Krupp et al. conducted a randomized clinical trial with the aim of determining whether the symptoms of PTLDS regressed under antibiotic therapy [16]. The 55 patients included were randomized to receive 28 days of parenteral ceftriaxone or placebo. Diarrhea, the primary adverse event, was more common in the ceftriaxone group than placebo. Four serious adverse events required hospitalization.
In the French observational study by Itani et al. the 15 patients had received an average of 6.8 antibiotics for 476 days [13]. Adverse events were reported in 4 patients.
In France, in 2020, Trautmman et al. analyzed the results of a survey sent to 3 French associations of patients with PTLDS who had taken Disulfiram [21]. Of the 16 patients who responded, 13 had experienced various and moderate side effects (headache, dizziness, difficulty concentrating, etc.).
In the United States, in 2018, Goodlet et al. analyzed adverse reactions to oral or IV therapy in patients with PTLDS for more than 6 months [23]. The incidence rates of adverse events was higher in the IV therapy group and there were more hospitalizations.
Case Reports
In Australia, in 2018 Johnstone et al. reported the case of a 41-year-old female patient who was treated with weekly glutathione infusions and phosphatidylcholine in a clinic for PTLDS [27]. The patient consulted the emergency department for bacterial sepsis.
In 2016, Issacs reported the case of a 15-year-old girl diagnosed by a general practitioner specializing in LB on the basis of serology performed in a private laboratory [28]. She suffered from chronic fatigue and was treated with 2 weeks of induced hyperthermia and intravenous antibiotics. These therapeutics induced severe dehydration due to Clostridium Difficile colitis.
In the United States, in 2019, Shelton et al. reported the case of a 32-year-old woman presenting to the emergency department with fever, confusion, and dyspnea [29]. For the past two years and a diagnosis of PTLDS, she had been treated with multiple oral anti-infectives. The emergency department diagnosed multifocal pneumonia following infection of her central venous catheter with Mycoplasma goodi. Catheter removal and parenteral and then oral antibiotic therapy resulted in clinical improvement.
In 2016, Marks et al. reported the case of a 45-year-old woman presenting to the emergency department with a pruritic, diffuse rash with nausea and fever [30]. Six months prior to her emergency visit she had been diagnosed with PTLDS with babesiosis. She had received multiple antibiotics over the past 3 months. Emergency department blood tests showed neither active Lyme disease nor babesiosis, but a DRESS syndrome. Her condition improved with corticosteroids.
In Belgium, in 2016, De Wilde et al. reported the case of a 76-year-old woman who consulted the emergency department for malaise, vomiting, anorexia and dyspnea [31]. In 2007, she had experienced facial paresis four weeks after the onset of erythema. In 2009, a private clinic diagnosed PTLDS. She was treated for 20 consecutive weeks with 4 g of ceftriaxone IV per day. A few years later, faced with a recurrence of symptoms, the doctors proposed eight weeks of treatment. Three weeks after the start of this treatment, the emergency department diagnosed ceftriaxone-induced immunohemolytic anemia. Discontinuation of the antibiotic resulted in improvement.