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65 Idiopathic Pulmonary Fibrosis Misdiagnosed asSputum-Negative Tuberculosis
483
large number of potential mimickers of IPF.Thus, a diagnostic algorithm (Fig.65.2)
and a specic set of evidence-based guidelines must be implemented to diagnose
and manage IPF [8].
Diagnostic Criteria [9]
1. Exclusion of all other known causes of interstitial lung disease (domestic and
occupational environmental exposures, connective tissue diseases, and drug
toxicity)
2. The presence of UIP (usual interstitial pneumonia) pattern (refer to Table65.2)
on HRCT (high-resolution computed tomography)
3. Specic combinations of HRCT and histopathologic pattern in patients sub-
jected to surgical lung biopsy
Fig. 65.2 Diagnostic algorithm for IPF. Source: https://link.springer.com/article/10.1007/
s12325- 018- 0857- z. UIP, usual interstitial pneumonia; HRCT, high-resolution computed tomogra-
phy; IPF, idiopathic pulmonary brosis; MDD, multidisciplinary discussion; BAL, bronchoalveolar lavage
484
Table 65.2 HRCT criteria for UIP pattern
HRCT criteria for UIP pattern
Possible UIP pattern (all 3
UIP pattern (all 4 features)
Predominant brosis in the
sub pleural and basal
compartment of lungs
Reticular Abnormality, often
heterogenous distribution
Honeycombing with or
without traction
bronchiectasis—present
Absence of features
inconsistent with UIP pattern
(refer column 3)
UIP, usual interstitial pneumonia; HRCT, high-resolution computed tomography
features)
Predominant brosis in the
sub pleural and basal
compartment of lungs
Reticular Abnormality
with often heterogenous
distribution
Absence of features
inconsistent with UIP
pattern (refer column 3)
Inconsistent UIP pattern (any of the
features)
Predominant brosis in the upper/
mid lung or in the
peribronchovascular areas of lung
Extensive ground glass abnormality
(extent > reticular abnormality)
Profuse micronodules (bilateral,
predominantly upper lobes)
Discrete cysts (multiple, bilateral,
away from areas of
honey-combing)
Diffuse mosaic attenuation/
air-trapping (bilateral and in ≥ 3
lobes)
A. Khan and J. L. Ferrero
Usual interstitial pneumonia (UIP) is more of a histopathologic term rather than
a disease and is often used interchangeably with IPF but not synonymous, as UIP is
often observed in many other diseases such as hypersensitivity pneumonitis, drug
toxicity, familial variants of IPF, etc.
Although UIP patterns on HRCT are suggestive of IPF in 50–60% of patients
with diffuse lung diseases [9], the remaining patients do not reveal a typical UIP
pattern that warrants a surgical lung biopsy for a denitive diagnosis. In most cases,
the specic histopathologic classication (refer to Table65.3) reveals a UIP pattern.
In some cases, the biopsies may be identied as non-classiable brosis (other than
the UIP pattern); thereafter the diagnosis is made after a cautious evaluation and
discussion by the multidisciplinary team (MDT).
The use of genetic and molecular biomarkers is also established in increasing the
precision of the diagnosis of IPF [4]. Thanks to the advancements in genetic and
molecular biomarker proling of IPF, several biomarkers have been identied and
classied based on their association with the underlying pathogenesis of the disease. Hence, analyzing the potential biomarkers of IPF may aid in diagnosing and
evaluating the prognosis/trajectory of the disease:
• A mutation in the TERT/TERC, MUC5B, peripheral blood markers such as
KL-6, surfactant protein SP-A, and SP-D are characteristics of telomere dys-
function that increase the epithelial cell’s susceptibility to injury in addition to
the impaired cell repair.
• Biomarkers such as CCL18, YKL-40, CXCL13, TLR-3, anti-HSP70, and
CD28CD4T cells are immune-mediated subtypes due to compromised innate
and adaptive immunity.
• Abnormal pulmonary remodeling mediated by biomarkers such as MMP1 and
MMP7, periostin, osteopontin, circulating brocytes, and markers of MMP
65 Idiopathic Pulmonary Fibrosis Misdiagnosed asSputum-Negative Tuberculosis
Table 65.3 Histopathologic criteria for UIP pattern
Histopathologic criteria for UIP pattern
UIP pattern (all 4
features) Probable UIP pattern
Dense brosis and
architectural distortion
with/without
honeycombing,
predominantly sub
pleural or paraseptal
distribution
Patchy brotic
inltration of the lung
parenchyma
Presence of broblastic
foci
Absence of features
against a diagnosis of
UIP suggesting an
alternate diagnosis (refer
column 4)
UIP, usual interstitial pneumonia; HRCT, high-resolution computed tomography
a
Can be associated with acute exacerbation of idiopathic pulmonary brosis
b
Isolated or occasional granuloma and/or mild form of organizing pneumonia may be found in lung
biopsied otherwise UIP pattern
Evidence of marked
brosis/architectural
distortion with/without
honeycombing
Absence of either
patchy involvement or
broblastic foci, but not
both
Absence of features
against diagnosis of
UIP suggesting
alternate diagnosis
(refer column 4) OR
Honey combing only
Possible UIP pattern
(all 3 features)
Patchy/Diffuse
brosis of the lung
parenchyma with/
without interstitial
inammation
Absence of other
criteria for UIP
(refer column 1)
Absence of features
except a diagnosis of
UIP or suggesting an
alternative diagnosis
(refer column 4)
Not UIP pattern (any
of the features)
Formation of
Hyaline membranes
Organizing
Pneumonia
Evidences of
Granulomas
Marked Interstitial
Inammatory cell
inltration away
from the regions of
honeycombing
Predominant airway
centered charges
Other features
suggestive of
alternative diagnosis
485
b
b
a
activity (generated by extracellular matrix turnover) may be an essential factor in
assessing the progression of the IPF.
The main challenges faced in the diagnosis of IPF are due to delays in diagnosis,
ruling out alternative diagnoses, and challenges faced in obtaining a surgical lung
biopsy [10]. Since IPF is a complex disease with a poor prognosis, early diagnosis
is essential, and delay in diagnosis poses a severe threat to the patient. The rationale
varies from the challenging nature of the patient to undergo a surgical biopsy to the
lack of experienced physicians. Hence all cases with suspected IPF are warranted
for referral to specialists, and this is a major obstacle among patients in underreserved areas where the accessibility to such specialists is laborious contributing to
diagnostic delay of the disease.
Management of IPF primarily focuses on improving the patient’s survival and
quality of life. Pirfenidone and nintedanib (tyrosine kinase inhibitors) are two antibrotic drugs approved for use in patients with IPF [7]. Although the medications
are not curative, they are essential in slowing the disease progression. A previously
used drug regimen known as triple immunosuppressive therapy for IPF (azathioprine, prednisolone, and N-acetylcysteine) has been discontinued due to the
increased incidence of hospitalizations and death [9]. In addition, PFT (pulmonary
function test) should be conducted every 3 to 6months based on the presentation of
486
A. Khan and J. L. Ferrero
symptoms and disease progression. Supportive therapy includes smoke cessation,
oxygen supplementation, proton pump inhibitors for GERD, and a pulmonary rehabilitation program including exercise training, occupational therapy, nutritional
changes, and social counseling.
Conclusion
The misdiagnosis of idiopathic pulmonary brosis (IPF) is well established among
the population with ILD, and an early diagnosis is evident in improving the prognosis of the disease. Physicians must conduct a thorough, comprehensive patient history (family and social) which aids in ruling out the differentials. Participation of a
multidisciplinary team (MDT) comprising pulmonologists, radiologists, pathologists with additional input from the occupational physician, and specialist nurse can
enhance the diagnosis of IPF, avoid unnecessary testing, and help optimize patient
management. Despite various challenges, extensive research in understanding the
underlying pathogenic mechanism and genetic studies in the future could help identify the cause(s) of IPF, detect disease in preclinical/early stages, help improve the
survival and quality of life, or in due course nd the ultimate cure for IPF.
References
1. Glasser SW, Hardie WD, Hagood JS. Pathogenesis of interstitial lung disease in children
and adults. Pediatr Allergy Immunol Pulmonol. 2010;23(1):9–14. https://doi.org/10.1089/
ped.2010.0004.
2. Barratt SL, Creamer A, Hayton C, Chaudhuri N.Idiopathic pulmonary brosis (IPF): an overview. J Clin Med. 2018;7(8):201. https://doi.org/10.3390/jcm7080201.
3. Isah MD, Abbas A, Abba AA, Umar M. Idiopathic pulmonary brosis misdiagnosed as
sputum-negative pulmonary tuberculosis. Ann Afr Med. 2016;15(4):204–6. https://doi.
org/10.4103/1596- 3519.194282.
4. Nakamura Y, Suda T.Idiopathic pulmonary brosis: diagnosis and clinical manifestations.
Clin Med Insights. 2015. https://doi.org/10.4137/CCRPM.S39897
5. Chung MJ, Goo JM, Im J-G.Pulmonary tuberculosis in patients with idiopathic pulmonary
brosis. Eur J Radiol. 2004;2:175–9. https://doi.org/10.1016/j.ejrad.2003.11.017.
6. Altaf Bachh A, Gupta R, Haq I, Varudkar HG. Diagnosing sputum/smear-negative pulmonary tuberculosis: does bre-optic bronchoscopy play a signicant role? Lung India.
2010;27(2):58–62. https://doi.org/10.4103/0970- 2113.63607.
7. Krishna R, Chapman K, Ullah S.Idiopathic pulmonary brosis. In: StatPearls. Treasure Island
(FL): StatPearls Publishing; 2022.
8. Raghu G, Collard HR, Egan JJ, etal. An ofcial ATS/ERS/JRS/ALAT statement: idiopathic
pulmonary brosis: evidence-based guidelines for diagnosis and management. Am J Respir
Crit Care Med. 2011;183(6):788–824. https://doi.org/10.1164/rccm.2009- 040GL.
65 Idiopathic Pulmonary Fibrosis Misdiagnosed asSputum-Negative Tuberculosis
9. Tomassetti S, Piciucchi S, Tantalocco P, Dubini A, Poletti V. The multidisciplinary approach
in the diagnosis of idiopathic pulmonary brosis: a patient case-based review. Eur Respir Rev.
2015;24(135):69–77. https://doi.org/10.1183/09059180.00011714.
10. Spagnolo P, Tonelli R, Cocconcelli E, Stefani A, Richeldi L. Idiopathic pulmonary brosis:
diagnostic pitfalls and therapeutic challenges. Multidiscip Respir Med. 2012;7(1):42. https://
doi.org/10.1186/2049- 6958- 7- 42.
487
Part XIV
Rheumatology
Chapter 66
How toDifferentiate Chronic Widespread
Pain inOrder toReduce Misdiagnosis
ofFibromyalgia
KoshaGeslaghi andBrandonKrout
Learning Objectives
By the end of this presentation, the clinician will be able to:
1. Discuss the clinical presentation of both FM and CWP.
2. Differentiate between FM and CWP through the clinical assessment chart provided by this chapter.
3. Enumerate the differential diagnoses and how to tell them apart from FM.
4. Analyze why FM is highly misdiagnosed.
Introduction
Despite extensive interest and examination over the past three decades, bromyalgia syndrome (FM) continues to insight debate and raise challenges at many fronts
of medicine [1, 2]. A few disputed and continually evolving points concerning FM
are the clinical usefulness and legitimacy of the diagnostic label FM, the nosological classication, diagnostic criteria, suggested etiology and pathophysiology, and
more [3–7]. The difculty of diagnosis, uncertainty between physical signs and
symptoms, and social stigma all contribute to an overall difculty by clinicians to
treat a patient with FM [17]. Now physicians are still reporting uncertainties about
how to diagnose FM [8, 9, 17]. This uncertainty translates into patient stressors,
frustration, and even dissatisfaction due to pain and lack of sleep caused by the
condition [10]. Further compounding the burden that FM places on patients is the
K. Geslaghi (*) · B. Krout
St. Martinus University Faculty of Medicine, Willemstad, Curacao
e-mail: kosha.geslaghi@martinus.edu; brandon.krout@martinus.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
H. Tohid et al. (eds.), The Misdiagnosis Casebook in Clinical Medicine,
https://doi.org/10.1007/978-3-031-28296-6_66
491
492
K. Geslaghi and B. Krout
time to establish a diagnosis. This process often extends to many years with many
clinic visits, investigations, invasive tests, and special consultations which all contribute to the personal, social, and nancial burdens of FM [9–11]. An early and
denitive diagnosis of FM has several advantages for each individual patient: the
diagnostic classication legitimizes the subjective symptoms and provides reassurance and peace of mind; patients are better able to manage with their health status
[9], and patients can access guidelines-based on their own treatments [12]. In contrast, there is increasing recognition of misdiagnosis of FM [13–15]. The aims of
this chapter overview are to outline the prevalence and potential reasons for the
misdiagnosis of FM and to give clinical guidance to enable the clinician to achieve
a more accurate diagnosis of FM, thus leading toward a more positive outcome for
the patient.
Clinical Case Presentation
There are a vast number of clinical situations that are associated with chronic widespread pain (CWP) . Therefore it is on the physician to always consider a differential diagnosis when evaluating a patient with a diffuse pain syndrome. The
differential diagnosis of CWP has been examined in detail in a recent review titled
appropriately “Diagnostic Confounders of Chronic Widespread Pain.” [16] In general, conditions that may share similarities with FM can be categorized into neurologic, non-rheumatic medical conditions, rheumatic, mental health disorders, and
drug-related negative effects. The conclusion of the review is that the misdiagnosis
of FM most likely occurs in the setting of early undiagnosed rheumatic diseases
before the appearance of abnormalities on physical exam or lab testings. For exam-
ple, preclinical rheumatoid arthritis could be present with body pain, fatigue, and
even muscle weakness in the months preceding onset of appreciable joint swelling
[17]. Polymyalgia rheumatica should always be considered in an older person presenting with a new onset of diffuse pain, although there is usually prominent stiffness and complaints are more focused toward the limb girdle regions. The early
stages of inammatory spondyloarthritis, especially in the setting of multiple sites
of enthesopathy [18], should be considered. Non-inammatory musculoskeletal
conditions should include myofascial pain syndromes. In the category of other medical illnesses, consideration of the following conditions should be given: endocrine
disease or metabolic disorder (hypothyroidism, hyperparathyroidism, acromegaly,
vitamin D deciency), gastrointestinal disease (celiac and non-gluten sensitivity),
infectious diseases (Lyme disease, hepatitis C, and immunodeciency disease), and
the early stages of a malignancy such as multiple myeloma, metastatic cancer, and
leukemia/lymphoma [16]. Neurological diseases with a pain component include
multiple sclerosis, Parkinson’s disease, and peripheral neuropathy. Spinal stenosis,
although most commonly associated with claudicant-type pain, can present in a
66 How to Differentiate Chronic Widespread Pain in Order to Reduce Misdiagnosis…
493
more ill-dened way and may be difcult for a patient to clearly describe. Even
though weakness is the most common symptom of myopathy, this may be less
prominent than diffuse pain in patients. Some cases have reported the misdiagnosis
of FM in patients with myopathies [19]. A medication history is always required in
diffuse pain, with an ever-growing list of drugs leading to myalgias and arthralgias.
The most common drugs are the statins, opioids, chemotherapeutic agents, aromatase inhibitors, and bisphosphonates [16]. The foundation for examining a patient
with CWP is an in-depth history and physical examination, which could be followed
by specically directed investigations as indicated in Table66.1 and Fig.66.1 [20].
Table 66.1 Fibromyalgia cues in the health history
Fibromyalgia cues in the health history
• Family history of early chronic pain, e.g., low back pain, “rheumatism,” etc.
• Personal history of pain in childhood and adolescence
• Long history of local pain
• Onset of widespread pain related to physical and/or psychosocial stress
• Pain characteristics that include neuropathic-like pain quality (burning pain). Aggravated by
weather changes, tension, poor sleep, stress
• General hypersensitivity to touch, smell, noise, taste
• Hypervigilance
• Multiple somatic symptoms (gastrointestinal, urology, gynecology, neurology) with previous
diagnosis of functional dyspepsia, irritable bowel syndrome, painful bladder syndrome,
tension headache, migraine, temporomandibular disorder
• High symptom-related emotional strain
Fig. 66.1 Decision-based approached thought web of clinical ndings for chronic widespread pain
494
K. Geslaghi and B. Krout
Differential Diagnosis
1. Myofascial pain syndrome—A chronic pain syndrome caused by muscle ten-
sion, injury, or repetitive motion and characterized by the presence of trigger
points in muscles and/or fascia (small tender knots).
2. Polymyalgia rheumatica—A chronic inammatory rheumatic disease of
unknown etiology that mainly affects women above the age of 50. Patients typically present with pain in their shoulders, hips, or neck; morning stiffness; and
systemic symptoms (e.g., fatigue, malaise, and depressed mood). Ten to twenty
percent of patients with polymyalgia rheumatica go on to develop giant cell
arteritis.
3. Hypothyroid myopathy—A complication of hypothyroidism that manifests as
proximal weakness with elevated creatine kinase levels. Clinically, the symptoms are very similar to those of polymyositis (progressive proximal muscle
weakness), so all patients with suspected polymyositis should be evaluated for
hypothyroidism.
4. Complex regional pain syndrome—A condition typically characterized by
severe, debilitating pain of the extremities with associated sensory, motor, and/
or autonomic changes. Typically associated with a specic precipitating trauma
and restricted to a specic nerve territory. The underlying mechanism is unknown
but thought to be related to inammation and dysfunction of pain perception.
What WasMisdiagnosed inThis Case andWhy?
Fibromyalgia is being misdiagnosed for a multiple of reasons, but the general reason why is that clinicians fail to observe the common clinical indicators of FM,
leading to the misdiagnosis of FM.
Discussion
The pillar for evaluating a patient with CWP is a comprehensive history and physical examination, which may be followed by specically directed investigations
(Table 66.1) [11]. History: As a rst step, the location of chronic pain can be
assessed. In the case of CWP, further questioning regarding associated symptoms
of tiredness even after sleep and fatigue should be looked at. Positive responses in
the setting of CWP would identify the condition as an FM-type syndrome. Attention
must be given to the timing of onset and evolution of symptoms, report of any triggering event, and alleviating or aggravating factors. In the context of FM’s familial
association, a family history of rst-degree relatives should be documented. For a
person presenting with CWP, especially as a new symptom, a medication history