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04/11/2023 Dr.T.V.Rao MD 1
Pyrexia of Unknown OriginPUO or FUO
Dr.T.V.Rao MD
04/11/2023 Dr.T.V.Rao MD 2
What is the normal human body temperature?
A. 37.5° CB. 98.6° FC. Each human being is a unique individual, and
therefore, normal temperature cannot be defined.
04/11/2023 Dr.T.V.Rao MD 3
What is the normal human body temperature?
A. 37.6° CB. 98.6° FC Each human being is a unique individual, and
therefore, normal temperature cannot be defined.
04/11/2023 Dr.T.V.Rao MD 4
Normal Body Temperature
• For healthy individuals 18 to 40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F)
• Low levels occur at 6 A.M. and higher levels at 4 to 6 P.M.
• The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.
• These values define the 99th percentile for healthy individuals.
Mackowiak, et al., JAMA 1992;268:1578
04/11/2023 Dr.T.V.Rao MD 5
Definition• Fever > 38.3 on
several occasions• Fever lasting
more than 3 weeks
• No diagnosis despite 1 week of inpatient workup
04/11/2023 Dr.T.V.Rao MD 6
Terminology• Old Definition:
1. Fever higher than 38.3oC on several occasions.
2. Duration of fever – 3 weeks3. Uncertain diagnosis after one week of study
in hospital• New Definition:
– Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital. … Ambulatory as well as in hospital
04/11/2023 Dr.T.V.Rao MD 7
Historical Causes of FUO• Hippocrates: excess of yellow bile• Middle Ages: demonic possession
(encephalitis?)• 18th Century: Friction associated with the
flow of blood through the vascular system and from fermentation and putrefaction occurring in the blood and intestines
04/11/2023 Dr.T.V.Rao MD 8
Definition Expansion1. Classical PUO2. Nosocomial
PUO3. Neutropenia
PUO4. HIV-Associated5. Transplant
04/11/2023 Dr.T.V.Rao MD 9
Categories of FUOFeature Nosocomial Neutropenic HIV-associated Classic
Patient’s situation
Hospitalized, acute care, no infection when admitted
Neutrophil count either <500/µL or expected to reach that level in 1-2 days
Confirmed HIV-positive
All others with fevers for ≥3 weeks
Duration of illness while investigated
3 daysb 3 daysb 3 daysb (or 4 weeks as outpatient)
3 daysb or 3+ outpatient visits
Examples Septic thrombophlebitis, sinusitis, C. difficile colitis, drug fever
Perianal infection, aspergillosis, candidemia
MAIc infection, TB, non-Hodgkin’s lymphoma, drug fever
Infections, malignancy, inflammatory diseases, drug fever
aAll require temperatures of ≥38.3°C (101°F) on several occasions.bIncludes at least 2 days’ incubation of microbiology cultures.cM. avium/M. intracellulare.
Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds): Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.
04/11/2023 Dr.T.V.Rao MD 10
Pattern of Fever
04/11/2023 Dr.T.V.Rao MD 11
Etiologies of PUO• Infection: Three major
causes• Abscess .. especially
occult ..• Intracellular
organisms. (salmonella mycobacterium, brucella)
• Intravascular … SBE
“True Fever”• Occurs when IL-1, IL-6, TNF-ά or other cytokines are
released from monocytes and macrophages in response to infection, tissue injury, drugs, and other inflammatory processes, increasing the body’s set point. The anterior hypothalamus maintains an inherent set point near 36ºC(98.6ºF).
• Normal circadian rhythm, which is highest(up to 2ºC, 3ºF) ~6pm and lowest at 6am. This accounts for increased volume of ER visits that peaks in the evening. Most true fevers follow this diurnal pattern.
04/11/2023 Dr.T.V.Rao MD 13
Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas,
etc)• Appendicitis, cholecystitis, tubo-ovarian
abscess, pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung
abscess• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
04/11/2023 Dr.T.V.Rao MD 14
Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas, etc)• Appendicitis, Cholecystitis, tubo-ovarian abscess,
pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung abscess• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
04/11/2023 Dr.T.V.Rao MD 15
Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas, etc)• Appendicitis, Cholecystitis, tubo-ovarian abscess,
pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung abscess• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
04/11/2023 Dr.T.V.Rao MD 16
Bacterial Pyrogens• Lipopolysaccharide (LPS)
endotoxinEndotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNFα.
• Staphylococcus aureus enterotoxins
04/11/2023 Dr.T.V.Rao MD 17
Infectious Causes of FUO
• Tuberculosis, Mycobacterium avium complex, syphilis, Q fever, Legionellosis
• Salmonellosis (including typhoid fever), Listeriosis, ehrlichiosis,
• Actinomycosis, nocardiosis, Whipple’s disease• Fungal (candidaemia, cryptococcosis, sporotrichosis,
Aspergillosis, Mucormycosis, Malassezia furfur)• Malaria, Babesiosis, toxoplasmosis, schistosomiasis,
fascioliasis, Toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasis
• Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus, parvovirus B19
04/11/2023 Dr.T.V.Rao MD 18
Miscellaneous Causes of FUO• Complex partial status epilepticus,
cerebrovascular accident, brain tumor, encephalitis
• Drug fever, Sweet’s syndrome, familial Mediterranean fever
• Gout, pseudo gout• Kawasaki’s syndrome, Kikuchi’s syndrome• Crohn’s disease, ulcerative colitis, sarcoidosis,
granulomatous hepatitis• Deep vein thrombosis• Atelectasis?
04/11/2023 Dr.T.V.Rao MD 19
Bacterial Pyrogens• Staphylococcus aureus toxic shock
syndrome toxin (TSST)Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-gamma in large amounts
• Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNFα but also IL1 and IL-6
04/11/2023 Dr.T.V.Rao MD 20
CAUSES CLASSIC PUO
• INFECTIVE 20-30%• CANCER 10-20%• AUTOIMMUNE 15-20%• MISC 15-25%• UNDIAGNOSED 5-10%
04/11/2023 Dr.T.V.Rao MD 21
Classic FUO
•Infection•Malignancy•Collagen vascular diseases
04/11/2023 Dr.T.V.Rao MD 22
Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas,
etc)• Appendicitis, cholecystitis, tubo-ovarian
abscess, pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung
abscess• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
04/11/2023 Dr.T.V.Rao MD 23
Infectious Causes of FUO
• Chronic pharyngitis, tracheobronchitis, lung abscess
• Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
04/11/2023 Dr.T.V.Rao MD 24
Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas,
etc)• Appendicitis, cholecystitis, tubo-ovarian
abscess, pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung
abscess• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
GeographyMalaria Saudi (malaria area)/Africa/India
Brucella Saudi/Gulf Area
Kala-Azar Yemen/Jazan/Sudan/India
Leprosy Yemen/Najran…
Typhoid India/Pakistan/Egypt/Indonesia
Histoplasmosis USA … (West Coast)
N.B.: Ease of Travel → Infection → All parts of the world.
Tuberculosis
All over the world.Liver Abscess
AIDS
04/11/2023 Dr.T.V.Rao MD 25
04/11/2023 Dr.T.V.Rao MD 26
04/11/2023 Dr.T.V.Rao MD 27
Pathophysiology• Meningitis and sepsis are serious etiologies
of fever in infants and young children. • Neonates' immature immune systems place
them at greater risk of systemic infection. Hematogenous spread of infection is most common in this age group or in patients who are immunocompromised. For these same reasons, infants who have a focal bacterial infection have a greater risk of developing sepsis.
04/11/2023 Dr.T.V.Rao MD 28
Bacterial Pyrogens• Lipopolysaccharide (LPS) endotoxin
Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNFα.
• Staphylococcus aureus enterotoxins• Staphylococcus aureus toxic shock syndrome toxin
(TSST)Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-gamma in large amounts
• Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNFα but also IL1 and IL-6
04/11/2023 Dr.T.V.Rao MD 29
What are common Causes• The following are among the most common bacterial etiologies of serious bacterial
infection in this age group:
• Streptococcus pneumoniae
• Group B streptococci
• Neisseria meningitidis
• Haemophilus influenzae type b
• Listeria monocytogenes
• Escherichia coli
04/11/2023 Dr.T.V.Rao MD 30
Consequences of Fever can be confusing
• Approximately 2.5-3% of highly febrile children younger than 3 years develop occult bacteremia, which typically is caused by S pneumoniae. Viral infections are common in the young child as well; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever.
04/11/2023 Dr.T.V.Rao MD 31
History Taking• Family History:
– Scrutinized for possible infectious or hereditary disorders• Tuberculosis• FMF
• Past Medical Condition:Lymphoma → may recurRheumatic Fever → may recurStill’s Disease → may recurBehcet’s Disease → may recur
• Exposure to sexual partner … Acute HIV• Illicit drug abuse (IV) … infective endocarditis,
Hepatitis … HIV
04/11/2023 Dr.T.V.Rao MD 32
Physical Examination….. Looking for the KEY physical sign …. Diagnostic yield60% in children (50%repeated)
• Document the Fever:– Significant and persistent for more than ONE occasion.
• Analyzing the Pattern:– Neither specific Nor sensitive enough to be considered diagnostic …
EXCEPT
Tertian & Quarter Pattern → MalariaPel-Ebstein Pattern → Lymphoma/
TuberculosisPulse-Temp Dissociation → Typhoid/
Brucellosis
04/11/2023 Dr.T.V.Rao MD 33
Infections
• Tuberculosis (especially extrapulmonary)Abdominal abscessesPelvic abscessesDental abscessesEndocarditisOsteomyelitis
04/11/2023 Dr.T.V.Rao MD 34
Infections• Sinusitis
CytomegalovirusEpstein-Barr virusHuman immunodeficiency virusLyme diseaseProstatitisSinusitis
04/11/2023 Dr.T.V.Rao MD 35
Etiologies of PUO• Infection
– Tuberculosis: .. Disseminated• The single most common infection in most PUO series
except in children and elderly.• Usually extrapulmonary or military, or• Occurs in the lungs and significant pre-existing lung
disease.• Pulmonary TB in AIDS is often subtle (normal chest x-
rays → 15 – 30%).• PPD is (+ve) < 50% of TB with PUO.• Diagnosis often requires Bx of LN/Liver/Bone marrow.• Sputum smear (+) only 25%
04/11/2023 Dr.T.V.Rao MD 36
Etiologies of PUO– Abscess:
• Usually located in abdomen or pelvis.• Secondary to appendicitis or diverticulitis.• Pyogenic liver abscess usually follow biliary tract
dis./abd. Suppuration.• Amoebic liver abscess is similar to pyogenic →
amoebic serology is positive > 95% of cases.• Splenic abscess is usually secondary to
hematogenous seeding.• Perinephric or renal abscess is usually secondary to
UTI.
04/11/2023 Dr.T.V.Rao MD 37
Etiologies of PUO– Bacterial Endocarditis
• Culture remains negative in 5% of patient.• Culture negative is likely with the following organisms:
– Coxiella burnetii → no growth.– HACEK group → incubate blood 7 – 21 days– Brucella } Special media/ – Legionelle } long time– Mycoplasm/Chlamydia }– Fungal → usually sterile
• Peripheral signs may not be detected.• Right-side Endocarditis → Lack murmurs → self
antibiotics → growth (-ve).
04/11/2023 Dr.T.V.Rao MD 38
Etiologies of PUO• Infection
– Tuberculosis: .. Disseminated• The single most common infection in most PUO series
except in children and elderly.• Usually extra pulmonary or military, or• Occurs in the lungs and significant pre-existing lung
disease.• Pulmonary TB in AIDS is often subtle (normal chest x-
rays → 15 – 30%).• PPD is (+ve) < 50% of TB with PUO.• Diagnosis often requires Bx of LN/Liver/Bone marrow.• Sputum smear (+) only 25%
GeographyMalaria Saudi (malaria area)/Africa/India
Brucella Saudi/Gulf Area
Kala-Azar Yemen/Jazan/Sudan/India
Leprosy Yemen/Najran…
Typhoid India/Pakistan/Egypt/Indonesia
Histoplasmosis USA … (West Coast)
N.B.: Ease of Travel → Infection → All parts of the world.
Tuberculosis
All over the world.Liver Abscess
AIDS
04/11/2023 Dr.T.V.Rao MD 39
04/11/2023 Dr.T.V.Rao MD 40
HIV associated PUO• HIV alone• TB,M avium/intracelulare• Toxoplasmosis• CMV ,PCP ,Salmonella• Cryptococcus, Histoplasmosis• Non Hodgkins Lymphoma• Drug induced
04/11/2023 Dr.T.V.Rao MD 41
Malignancies• Chronic leukemia
LymphomaMetastatic cancersRenal cell carcinomaColon carcinomaHepatomaMyelodysplastic syndromesPancreatic carcinomaSarcomas
04/11/2023 Dr.T.V.Rao MD 42
Autoimmune Conditions with Fever
• Adult Still's diseasePolymyalgia rheumaticTemporal arteritisRheumatoid arthritisRheumatoid feverInflammatory bowel diseaseReiter's syndromeSystemic lupus erythematousVasculitides
04/11/2023 Dr.T.V.Rao MD 43
Miscellaneous• Drug-induced fever
Complications from cirrhosisFactitious feverHepatitis (alcoholic, granulomatous, or lupoid)Deep venous thrombosisSarcoidosis
04/11/2023 Dr.T.V.Rao MD 44
Diagnosis
• A cost-effective individualized approach is essential in the evaluation of these patients to prevent performing inappropriate tests.
04/11/2023 Dr.T.V.Rao MD 45
Minimal Initial Diagnostic Workup For FUO
• Comprehensive history• Physical examination• CBC + differential• Blood film reviewed by hematopathologist• Routine blood chemistry• UA and microscopy• Blood (x 3) and urine cultures• Antinuclear antibodies, rheumatoid factor• HIV antibody• CMV IgM antibodies; heterophile antibody test (if c/w mono-like
syndrome)• Q-fever serology (if risk factors)• Chest radiography• Hepatitis serology (if abnormal LFTs)
Mourad, et al. Arch Intern Med. 2003;163:545
04/11/2023 Dr.T.V.Rao MD 46
Diagnostic TestingBlind application leads to excessive falsetests …• Complete Blood Count
– Anemia if present → suggest a serious underlying disease– Leukocytosis with bands → occult bacterial infection– Lymphocytosis & atypical Lymphocyte → Infectious
mononucleosis– Leucopenia and Lymphopenia → advanced HIV– Leukoerythroblastic Anemia → Disseminated TB– Thrombocytopenia → Malaria/Leukemia– Peripheral Blood → Malaria
04/11/2023 Dr.T.V.Rao MD 47
Diagnostic Testing• Urinalysis, Urine Culture, U/E, LFT• ESR
– If elevated → significant inflammatory process
– Greatest use in establishing a serious underlying disease, esp. if v. high → ESR > 100 mm/h …Tuberculosis … m myeloma … temporal arteritis
04/11/2023 Dr.T.V.Rao MD 48
Diagnostic Testing– 58% → malignancy → Lymphoma/myeloma– 25%
• Infection – Endocarditis• Giant cell arteritis
– ↑ High ESR → lacks specificity:• Drug Reaction }• Thrombophlebitis } may cause very high ESR• Nephrotic Syndrome }
– Normal ESR → significant inflammatory process is absent with exception.
04/11/2023 Dr.T.V.Rao MD 49
Diagnostic Testing• CRP-closely associated with inflammatory
process– Not invariable components of the febrile response.– Usually does not go up with viral infection.* ESR & CRP is elevated in:
1. Bacterial Infection2. Neoplasm3. Immunological-mediated inflammatory states4. Tissue infarction
04/11/2023 Dr.T.V.Rao MD 50
Diagnostic Testing• Acute Phase Proteins
Proteins Increased Proteins Decreased
Fibrinogen Albumin
Ferritin Transferrin
Plasminogen Alpha-
Fetoprotein
Protein S
Cerruloplasmin
New England J Med. 1999, 340.448-454
04/11/2023 Dr.T.V.Rao MD 51
Diagnostic Testing• Blood Testing
– Anti-nuclear Antibodies– Rheumatoid Factor– CMV Antibody … IgM– Heterophile Antibody Test in children and young
adult– Tuberculin Skin Test … 5 unit ID– Thyroid Function Test– HIV Screening
04/11/2023 Dr.T.V.Rao MD 52
Diagnostic Testing• Imaging Studies: … to localize abnormalities
for definite tests or treatment– Chest x-ray:
• Military shadows → disseminated tuberculosis• Atelectasis } 1. Liver
↑ Hemi diaphragm } Abscess 2. SpleenPleural Effusion } 3. Pancreatic
4. Subphrenic• Mediastinal mass → Lymphoma/Tuberculosis/ Sarcoid• If CXR is (N) → Repeat on weekly basis
04/11/2023 Dr.T.V.Rao MD 53
Diagnostic Testing– CT-Scan → CT scan chest
• Mediastinal mass → Tuberculosis/Lymphoma/ Sarcoidosis
• Dorsal Spine → Spondylitis and disc space disease
• CT-Scan Abdomen → very effective to visualize– All types of abscesses– Retroperitoneal tumor, lymph node or hematoma
– MRI: spleen, lymph node and the brain
04/11/2023 Dr.T.V.Rao MD 54
Diagnostic Testing• Serology Test
– Brucella Titer– CMV & EBV antibody test– HIV testing (Elisa screening)– ANF
• Radio nuclear Scanning– Bone TC-scan → osteomyelitis (skeletal)– Gallium scan → occult inflammation– Indium labeled WBC-scan → occult abscesses
04/11/2023 Dr.T.V.Rao MD 55
Diagnostic Testing– Hepatomegaly or Abnormal LFT
• Hepatic Granuloma– Non-caseating: Tuberculosis/Sarcoidosis & Brucellosis– Caseating: Tuberculosis
– Bone Marrow• Granuloma ± Tubercle Bacilli → Tuberculosis• Aplastic Cells → Leukemia• Leishmania Bodies → Kala-Azar• Atypical Cells → Lymphoma• Atypical Plasma Cells → M. myeloma
– Temporal Artery → Giant Cell Arteritis– Pleural or Pericardial → Extrapulmonary Tuberculosis
04/11/2023 Dr.T.V.Rao MD 56
Investigation • Blood culture before the
antibiotics• Culturing of Urine• Sputum culture• Stool examination for Bacterial
and Parasitic infection.
04/11/2023 Dr.T.V.Rao MD 57
Etiologies of PUO– Abscess:
• Usually located in abdomen or pelvis.• Secondary to appendicitis or diverticulitis.• Pyogenic liver abscess usually follow biliary tract
dis./abd. Suppuration.• Amoebic liver abscess is similar to pyogenic →
amoebic serology is positive > 95% of cases.• Splenic abscess is usually secondary to
haematogenous seeding.• Perinephric or renal abscess is usually secondary to
UTI.
04/11/2023 Dr.T.V.Rao MD 58
Tuberculosis• Sputum
examination for AFB
• Culturing for AFB• Monteux test
Tuberculin test• X ray of the chest
04/11/2023 Dr.T.V.Rao MD 59
Diagnosis• More invasive testing, such as LP or biopsy
of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation.
• When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful.
04/11/2023 Dr.T.V.Rao MD 60
Etiologies of PUO• Factitious Fever
Febrile PUOIn one study … 9% of cases of PUO– False fever: thermometer manipulation using external heat
or substitute thermometer. Men use this way … physician are rare for this disorder. Increasing somewhat in elderly … 115 … 116 …
– Genuine fever (self induced) Administration of pyrogenic substances (bacterial
suspensions) Generally young women with connection to health care …
often NURSES.
04/11/2023 Dr.T.V.Rao MD 61
Pyrexia of Unknown Origin
The majority of disease remaining after aninitial NEGATIVE work-up are:
1. Neoplasm2. Seronegative Collagen Vascular Disease3. Increasing Tuberculosis4. Increasing Drug Addition5. Elderly with Endocarditis6. HIV with or without infection or malignancy7. Implanted prosthetic devices8. Travel … New Exposure
04/11/2023 Dr.T.V.Rao MD 62
Therapeutic Trials• Limitation and risk of empirical therapeutic
trials:– Rarely specific– Underlying disease may remit spontaneously false
impression of success.– Disease may respond partially and this may lead to
delay in specific diagnosis.– Side effect of the drugs can be misleading.
04/11/2023 Dr.T.V.Rao MD 63
Therapeutic Trials• What is the best
therapy for PUO patient?– To hold therapeutic trials
in the early stage… except in:
• Patient who is very sick to wait.
• All tests have failed to uncover the etiology.
04/11/2023 Dr.T.V.Rao MD 64
Prognosis• Prognosis is determined primarily by
the underlying disease.• Outcome is worst for neoplasms.• FUO patients who remain undiagnosed
after extensive evaluation generally have a favorable outcome and the fever usually resolves after 4-5 weeks.
Larson et al. Medicine 1982;61:269
04/11/2023 Dr.T.V.Rao MD 65
Summary• FUO is often a diagnostic dilemma• Infections comprise ~30% of cases• Bone marrow biopsies are of low
diagnostic yield• Diagnostic approach should occur in a
step-wise fashion based on the H&P• Patient’s that remain undiagnosed generally
have a good prognosis
04/11/2023 Dr.T.V.Rao MD 66
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