Narges presented a case of a late-middle age woman with history of recurrent pancreatitis, chronic alcohol use, who presents with worsening leg swelling, nausea/vomiting, and chest pain in setting of increased alcohol intake from bereavement. She increased her alcohol intake from “several drinks” a day to a fifth of hard liquor per day for the past few weeks. She was incidentally found to have a severely elevated Transferrin Sat, and genetics study revealed HFE mutation consistent with hemochromatosis.
For those of us illiterate in EtOH… A standard drink is defined as:
- Hereditary: Up to 10% of Caucasians in US and Western Europe are thought to be heterozygous. Homozygous roughly 0.5%.
- Symptomatic median age around age 40 for males, later for females due to higher iron loss.
- Disorder of iron storage, that results in increased intestinal iron absorption and iron deposition.
- Iron deposition leads to organ damage.
- Hereditary form
- Most commonly secondary to mutant HFE (human hemochromatosis protein).
- HFE codes a protein involved in cellular iron sensing and intestinal iron absorption regulation.
- Autosomal recessive with variable penetrance.
- Heterozygotes are asymptomatic and are not at risk of iron-overload.
- Homozygous patients have variable disease penetrance, thought to be relatively low.
- ***Key point: Just because someone has the mutation (can be incidentally found on genetic sequencing) does not mean they will have the disease (iron build up in the body leading to end organ damage).
- Alcohol intake is a major risk factor for development of liver disease for patients with HFE mutation. Iron overload thought to potentiate effect of alcohol induced liver toxicity
- Liver damage occurs without inflammation, but hence HH can occur in setting without elevated AST/ALT.
- At least 43% of HH pts have other underlying causes i.e. fatty liver, alcohol, HBV/HCV, that leads to elevated transaminases and liver cirrhosis.
- Most common mutant is C282Y, if heterozygous, not at risk for developing progressive or symptomatic iron overload.
- Homozygous C282Y are at risk but again penetrance is variable.
- Homozygous H63D are generally not at risk but might have minor abnormalities in iron studies. If symptomatic, usually has other underlying process i.e. alcohol (such as this patient).
- Secondary iron overload (seen in frequent transfusions due to ineffective erythropoiesis)
- Takes time to develop end-organ damage. Patients are usually asymptomatic until they have 20+ g of iron built up in the body (average iron content of an adult is 4-5g).
- Early: Non-specific, weakness, weight loss, skin hyperpigmentation (bronze skin), abd pain, loss of libido.
- Later: Hepatomegaly (95%), cirrhosis, HCC
- Other organs:
- DM (50%, pancreas) chronic pancreatitis (advanced hemochromatosis)
- Hypogonadism (ovaries, testes), impotence/infertility
- Hypothyroidism (thyroid)
- Adrenal insufficiency (adrenals)
- Arthralgia (joints, CPPD pseudogout), osteoporosis (pan hypopit leading to secondary hypogonadism)
- Heart (heart failure, enlargement)
- Pan-hypopit (pituitary)
- Listeria, Yersinia, and Vibrio sp have increased in an iron rich environment. Mucor sp also favors an iron-rich environment
- Labs: Inc Fe, % transferrin sat, and serum ferritin levels.
- Healthy pt: Fasting serum transferrin sat > 50% is abnormal and possibly suggestive of underlying hemochromatosis.
- Serum transferrin sat: PPV of 26-39%, 80% if two separate, positive tests. NPV of 100%
- Ferritin levels: not that useful, acute phase reactant, can fluctuate.
- Remove excess iron!
- Intermittent phlebotomy, goal serum iron 50-100mcg/dL
- 1 unit of blood = 250mg Fe, hence to get 20g of iron town to a relatively normal level via phlebotomy, this might take 2-3 years.
- Chelating agents: Deferoxamine, less effective compared to weekly phlebotomy strategy but indicated in instances when you cannot do phlebotomy, i.e. anemia.
- IF caught early, organ damage is reversible with iron removal
- If cirrhosis has set in, this increases risk of hepatocellular carcinoma by 20-200 fold.
- All 1st degree family members of a patient with confirmed hemochromatosis should be screened with a genetics study +/- an iron panel.
- Per AASLD 2011 Guideline:
Thanks to Arathi for presenting the case of a middle-aged man with poorly controlled diabetes who presented with blurry vision and ear pain, found to have multiple cranial nerve palsies, diagnosed with skull base osteo, septic dural sinus thrombosis, and orbital cellulitis!
- Septic thrombophlebitis is venous thrombosis with inflammation in the setting of bacteremia and can impact any vein. Most common cause of this condition in the hospitalized patient is indwelling lines and catheters.
- Septic thrombophlebitis of the jugular vein is called Lemierre’s syndrome and is frequently preceded by pharyngitis.
- Septic dural sinus thrombosis is extremely rare (only several hundred cases diagnosed in recent history). The most common presenting symptom is headache. There are three types:
- Cavernous sinus thrombosis
- Lateral (transverse) sinus thrombosis (rare)
- Superior sagittal sinus thrombosis (very rare)
- Cavernous sinus thrombosis can present with CN III, IV, V1, V2, VI palsies. Of these, CN VI is the first one to get affected. So for patients presenting with lateral gaze palsy and headache, think cavernous sinus thrombosis!
- The mainstay of treatment for septic dural sinus thrombosis is antibiotics. Most common organism involved is staph aureus.
- The role of anticoagulation is controversial. The few retrospective studies done have shown a potential reduction in mortality/morbidity without a significant increase in risk of ICH. Common practice currently is to start anticoagulation with heparin early on especially in patients with unilateral symptoms.
Septic dural sinus thrombosis
- Uncommon disease with only several hundred cases reported in the antibiotic era. So you might only see one in your whole career!
- Difficult to diagnose and often diagnosis and treatment are delayed.
- Encompasses three basic syndromes: manifestations of each are unique
- Cavernous sinus thrombosis
- Lateral sinus thrombosis
- Superior sagittal sinus thrombosis
- All three manifest as severe headaches which are often the presenting symptom.
Septic cavernous sinus thrombosis
- Most common. Lots of trabeculae to trap bacteria.
- Clinical manifestations
- Headache and cranial nerve palsies should raise your suspicion!
- Fever, periorbital edema. Pain is usually unilateral, retroorbital and frontal in nature with radiation to the occiput.
- Altered mental status especially in older people
- Less common: photophobia, tearing, and ptosis
- B/l ptosis, proptosis, chemosis, and ocular muscle paralysis but can be subtle
- Fundoscopic exam with papilledema
- Lateral gaze palsy (isolated CN VI) is the first manifestation because of the location of the nerve in the cavernous sinus.
- Loss of visual acuity from papilledema
- Compression of optic nerve by mycotic aneurysm of the intercavernous segment of the internal carotid/ophthalmic artery can lead to blindness.
- CSF can show inflammatory cells in 75% of cases.
- Staph aureus is the most common (70%) followed by strep and anaerobes.
- CT venogram or MR venogram
- Antibiotics: IV and prolonged for at least 3 weeks b/c thrombus may prevent abx penetration
- Anticoagulation: No prospective data. One retrospective study showed a significant reduction in mortality in patients with unilateral involvement who presented early and received heparin. A second showed no change in mortality but decreased morbidity. No increased risk of ICH. Based on these small studies, experts suggest heparin early on in patients with unilateral CST. Duration of anticoagulation is at the discretion of the clinician (no data).
- Surgery: Drainage of sinus infection if present, otherwise no benefit.
- No role for steroids
- Mortality is 30%
- Infection can spread to meninges and the pituitary and morbidity can reach 50%.
- 30% suffer serious sequelae:
- Persistent oculomotor weakness
- Pituitary insufficiency
Septic lateral sinus thrombosis
- Rare due to early treatment of otitis media. Generally results from untreated OM à mastoiditis à lateral sinus thrombosis.
- Earache is generally the first symptom for several weeks
Septic superior sagittal sinus thrombosis
- Extremely rare
- Usually due to bacterial meningitis
- Complete thrombosis is universally fatal.
Differential for cavernous sinus obstruction:
- septic thrombosis
- intra-orbital abscess
- Tolosa-Hunt syndrome (granulomatous inflammation of the superior orbital vein and cavernous sinus)
- Polyarteritis nodosa (Cogan syndrome)
- IgG4 dz
- Nasopharyngeal tumor
Skull base osteomyelitis:
- Frequently seen in elderly patients with poorly controlled diabetes or immunocompromise
- Most commonly a complication of malignant otitis externa.
- Results in multiple cranial nerve palsies VII through XII due to involvement of the stylomastoid, jugular, and hypoglossal foramens.
- Treatment requires antibiotics for at least 4-6 weeks.
Ernest presented a case of a young woman, with no medical history, presenting with acute onset severe mucositis (eyes, mouth, urogenital) after a few days of viral prodrome and one day after taking azithromycin prescribed by her PCP. Her skin findings were almost non-existent and the bulk of her symptoms were isolated to the mucosa. Her presentation is consistent with a diagnosis of MIRM!
MIRM (Mycoplasma Induced Rash and Mucositis)
- 25% of patients with mycoplasma pneumoniae experience extra-pulm manifestations
- Coined different terms, incomplete SJS, Fuchs Syndrome, MIRM
- Mean age: Young (median 11-12 yo), male predominance.
- Universally will have some sort of prodrome: cough, malaise, fever preceding eruption of lesions by ~ 1 week.
- Manifestations: variable, mucositis alone, prominent mucositis with sparse skin involvement. Skin involvement tends to be very rare and on the milder side, presenting as vesiculobullous, targetoid, papules, macules. Rarely morbilliform.
- Majority of cases are severe mucositis alone.
- Involvement: Oral (100%), ocular (92%), urogenital (78%)
- Clinical Dx
- Mycoplasma IgM/IgG helps but their sensitivity and specificity are highly variable.
Supportive care (especially pain control, hydration/nutrition, infection prevention) plus treat the underlying cause (mycoplasma)!
- Systemic corticosteroids (mixed data so generally not recommended first line)
- IVIG (has been used in very severe cases))
- Better than SJS/TEN, 81% will make a full recovery.
- Blindness/residual visual impairment is possible but less common vs SJS/TEN
Key distinguishing features:
MIRM: Young, slight male preference, usually 7 days after infection, predominantly mucosal involvement, very little cutaneous involvement, better prognosis vs SJS/TEN.
SJS/TEN: Any age, female preference, usually 1-3 weeks after drug exposure, diffused skin involvement (Nikolsky sign) + mucosal involvement, more severe ocular manifestation.
Please refer to this review article for more background on this condition.
Thanks to Joe for presenting the fascinating case of a middle-aged man who presented with AMS and SIRS, found to have a LP findings concerning for aseptic/viral meningitis with a negative work up and persistent fevers, eventually found to have a swollen joint which was tapped and synovial fluid sample sent for 16s rDNA showing streptobacillus moniliformis, also known as Rat Bite Fever!
- The predominant cell type found in CSF of patients with viral or aseptic meningitis is monocytes and PMNs
- Traumatic LPs result in blood seeping into the CSF fluid sample. To correct for a traumatic LP, subtract 1 WBC for every 1000 RBCs in the tube.
- Most common causes of aseptic meningitis are enteroviruses (Coxsackievirus and echovirus).
- Most common cause of proven viral encephalitis in the US is West Nile Virus (remember that it presents with flaccid paralysis first and is often confused for GBS).
- The most commonly used OTC medications associated with aseptic meningitis are NSAIDs.
- While >90% of rodents are estimated to carry streptobacillus moniliformis (bacteria causing Rat Bite Fever), rate of transmission to humans after a bite is ~10%.
- Streptobacillus moniliformis does not grow on routine cultures. 16s rDNA gene sequencing (AKA universal PCR) can be sent on synovial fluid or tissue to establish the diagnosis.
CSF fluid findings in various diseases
Figure above adapted from the UpToDate and the UCSF Hospitalist Handbook.
Fever of unknown origin (FUO): Our patient did not meet this definition, but just for review
- Defined as T >38.3 on several occasions over 3 weeks and failure to diagnose after 3 days of hospitalization or three outpatient visits
- Infectious (~1/3): intra-abdominal, abscesses (dental, pelvic), culture-negative endocarditis, TB, lyme, C diff, prostatitis, EBV, CMV, HIV
- Autoimmune (~1/3): Still’s, seronegative spondy, lupus, cryo, PAN, GPA
- Malignancy (~20%): lymphoma, leukemia, sarcoma, mets, MDS, pancreatic, colon, RCC
- Other: drug reaction, alcoholic hepatitis, ETOH w/d, toxic ingestion, central or factitious fever
- Undiagnosed (~20%)
- Nosocomial: PE, line infection, transfusion related, C diff, drug fever
Rat Bite Fever (RBF)
- Only 17 cases between 2000 and 2012 identified in California
- Many cases go undiagnosed since it’s not a nationally notifiable disease and b/c the bacteria responds to empiric antibiotic therapy.
- Risk of getting the infection after a rate bite is 10% (20,000 rat bites occur in the US/year)
- At risk populations are pet store workers, lab techs, and people living in poverty
- Fun fact: in Asia, RBF is known as sodoku.
- Streptobacillus moniliformis is the most common cause in the US
- Pleomorphic fastidious branching gram negative bacillus
- Stains irregularly so can be mistaken for gram positive
- Bacteria require specific media for isolation and incubation in a high CO2 environment
- Grows slowly so if suspicious, hold onto cultures for at least 7 days
- Found in the nasal and oropharyngeal flora of rats and other rodents that are asymptomatic. High rate of carriage.
- Can result from bite or scratch or from ingestion of food or water contaminated with infected rat feces (latter is called Haverhill Fever, named after town in Massachusetts where the illness developed after consumption of contaminated unpasteurized milk)
- Clinical manifestations:
- Ranges from mild flu-like illness (more common) to fulminant sepsis in children and adults
- Mortality is 13% in untreated patients
- Incubation period is <7 days
- Abrupt onset of fever, myalgias, migratory arthralgias (typically of the knees but can go to elbows, wrists, shoulders, and hips as well), vomiting, pharyngitis, and headache
- Bite wound has usually resolved by the time of presentation
- No regional adenopathy
- Can be accompanied by a maculopapular rash on extensor surfaces and palms/soles
- Vomiting and pharyngitis are more common with ingestion
- Arthritis may relapse or persist for years and sometimes pathogenic bacteria can persist in joints for months despite clearance of the organism from blood and other sites.
- Meningitis (as with our patient)
- Focal abscesses
- Septic arthritis (as with our patient)
- Multiorgan failure
- No serologic test is available
- Analysis of 16s rDNA gene sequence has been used for diagnosis on appropriate specimens
- Not available for blood but can be done on synovial fluid or tissue.
- Dx is empirically made in patients with unexplained febrile illness or sepsis and a history of rat exposure, especially if relapsing or intermittent fever pattern and joint involvement.
- No good studies on the disease to help us determine duration because of paucity of cases
- For severe cases, treatment mimics endocarditis
- Avoid rats
- If rat bite, then give a three-day course of oral PCN V 500 mg QID. Efficacy of this approach however is unknown
Thank you Charles for presenting this really interesting case. A 18 year old woman with a history of asymptomatic thrombocytopenia who presents with several days of non-specific fever, chills, malaise, mild shortness of breath and she was found to have acute anemia, thrombocytopenia, elevated transaminitis, and patchy bilateral pulmonary infiltrates on CXR during initial presentation. She became acutely ill with submassive hemoptysis and went into respiratory failure in 24-48 hours. She was found to have DAH on BAL. Her autoimmune and infectious work up came back negative, but her ferritin came back at 75776. Base on this and her constellation of symptoms, further work up revealed a 6/8 criteria for diagnosis of hemophagocytic lymphohistiocytosis!
- Dyspnea, cough fever, respiratory failure, acute anemia
- Hemoptysis only in 2/3 of cases
- Definition: Hemoptysis, diffuse alveolar infiltrates, acute anemia, and hypoxemic respiratory failure
- Widespread damage to pulmonary small vessels, leading to blood within the alveoli eventually causing impaired gas exchange.
- Causes: Autoimmune/connective tissue disease leading to pulmonary vasculitis (ANCA, anti-GBM), certain pulmonary infections, toxins, drug reactions, mitral stenosis in some cases
- 3 distinct histologic subtypes that can give hints to underlying pathology
- Most common: Pulmonary capillaritis: ANCA vasculitis, GPA, EPGA, pauci-immune, Goodpasture, HSP, SLE, RA, APLS, MCTD, Behcet, drug-induced, lung transplant rejection, etc.
- Systemic vasculitis manifestation
- Bland pulmonary hemorrhage: Coagulopathy, mitral stenosis, toxin/inhalation, SLE, drugs, Goodpasture
- Anti-GBM, SLE, no inflammation or destruction of capillaries but RBC leakage
- Diffuse alveolar damage: BM transplantation, radiation, ARDS, cytotoxic drugs, other causes
- CXR: Diffuse bilateral alveolar infiltrates, no pathognomonic findings
- BAL: serial bloody aspirate with sequential sampling
- CT: Non-specific GGO
- Biopsy: Tissue biopsy of the lung is definitive in confirmation of DAH but underlying cause might not be revealed.
- Treat underlying cause
- Respiratory support, most patients die from respiratory failure
- High dose corticosteroids, i.e. methylprednisolone up to 500mg Q6H (up to 2g daily)
- Other agents: Cyclophosphamide, azathioprine, MTX, mycophenolate, etanercept.
- Plasmapheresis for Goodpasture or vasculitidies.
- Key: Early identification and treatment
- Worldwide incidence is unknown, not enough data available, thought to be rare AND underrecognized but growing recognitive leads to higher incidence.
- Familial types: more common to occur in pts < 18yo
- Secondary HLH: any age
- Uncontrolled hyperinflammatory response with dysregulated macrophage activity leading to excessive cytokine production
- Primary: HLH due to an underlying genetic abnormality or without clear cause
- Autosomal recessive familial HLH
- Secondary: Due to something else
- Retrospective study at Mayo in 2014:
- Infection (34%), most commonly EBV
- Autoimmune (8%), Macrophage activation syndrome (MAS), most often associated with AOSD, systemic juvenile idiopathic arthritis, or SLE.
- Malignancy (52%) NHL, HL, acute leukemia
- Idiopathic/Immune deficiency/other (6%)
- Fever, splenomegaly, cytopenias are most common
- + manifestation of the trigger
- Complications: Infection, DIC, bleeding complications (reports of intracranial hemorrhage, GIB, DAH), end organ damage.
Diagnosis: Per the Histiocyte Society: 5/8 criteria for diagnosis. In case you cannot remember all 8, please refer here for the famous HLH Song by Dr. Eric Lau:
- Peripheral cytopenia (> 2 cell lines)
- Hypertriglyceridemia or Hypofibrinogenemia
- Elevated ferritin > 500 (> 10000 = 90% sensitive and 96% specific for HLH)
- Low NK cell activity
- Elevated soluble CD25 (soluble IL2-R)
- Hemophagocytosis in BM, spleen, or LN: Only seen in later course of the diseases and not required for the diagnosis, neither sensitive nor specific, can be seen in severe sepsis/critical illness)
- Like all things in medicine, treat the underlying cause
- Current treatment is based on the HLH-94 study on pediatric population
- Induction: 8 weeks dexamethasone and etoposide.
- Maintenance: Cyclosporine, tacrolimus, dex pulses
- If MAS: Steroids alone, usually responsive.
- Hematopoietic stem cell transplant is refractory/relapsing.
For more information on HLH, please refer to this article by Dr. Schram and Dr. Berliner published in Blood (as in the journal) in 2015.
Thanks to Julie for presenting the case of a middle-aged man with recent CAP who presented with progressive SOB, pleuritic chest pain, weight loss, and anorexia, found to be septic with a large empyema, eventually requiring open decortication!
- Think of parapneumonic effusions in two broad categories: infected (complicated and empyema) and sterile (uncomplicated).
- Infected (complicated and empyema) require chest tube placement and can be complicated by loculated effusions.
- Uncomplicated resolve with the treatment of underlying pneumonia
- Anaerobic organisms are a common cause of infected parapneumonic effusions. Malodorous fluid at the time of thoracentesis is diagnostic! But make sure to send anaerobic cultures to the lab to help with speciation.
- pH of pleural fluid can be falsely elevated if not immediately stored on ice upon collection and processed in a blood gas analyzer.
- Differential for pleural fluid that has low glucose/low pH is short: infection, TB, malignancy, rheumatoid pleurisy, and lupus pleuritis.
- Remember that while ADA has high sensitivity (86%) and high specificity (87%) for TB, the study on which it is based was done in a high risk population so its utility in screening low risk patients is limited.
- Form in 40% of bacterial pneumonia:
- Uncomplicated: negative GS and Cx, pH>7.2, glucose >60, no loculations
- Complicated: positive GS or Cx or pH <7.2, or glucose <60. LDH >1000 makes it more likely
- Empyema: frank pus aspirated during thora, cell count with >50k WBCs
The latter two categories require chest tube placement to prevent formation of pleural “peels” that can lead to trapped lung and loss of lung function.
- Lateral decub or ultrasound, latter is more sensitive than CXR for diagnosing complicated parapneumonic effusions.
- CT with contrast is the optimal imaging for empyema or loculated effusion
- Look for the “split pleura sign”
- Serum procalcitonin >0.18 ng/mL is 83% sensitive and 81% specific for effusion having a bacterial infectious etiology
- Anaerobic bugs are often the culprit! So it is important to send pleural fluid for both aerobic and anaerobic cultures
- Other bacteria: CAP organisms such as strep and staph as well as klebsiella in diabetic patients
- Tube thoracostomy (chest tube): first intervention
- CT within 24 hours to ensure correct positioning and adequate drainage, left in place until drainage is <50 cc/day
- Fibrinolytic agents
- DNA is a main contributor to viscosity of empyema fluid. However, based on this trial published in NEJM in 2011, tPA and DNAase combined is associated with significant radiographic improvement of empyema, reduction in hospital stay, and lower number of surgical referrals.
- To remove the thickened fibrin layer covering the pleura.
- Open thoracostomy
- Rib resection and opening the chest wall at the inferior border of empyema to allow for ongoing drainage. High risk of infection and complications.
Thanks to Naina for presenting the case of an elderly man presenting with acute onset of n/v, and abdominal pain, found to have anemia and AKI, with work up revealing small cell cancer of the bladder causing ureteral obstruction with mets to the lymph nodes, liver, lung, and bone, hospitalization complicated by TLS prior to onset of chemo and contrast induced nephropathy.
- Bladder cancer is the most common malignancy of the urinary system and urothelial (transitional cell) carcinoma is the culprit >90% of the time. Less common subtypes include squamous, adeno, small cell (our patient), and sarcoma.
- Unexplained hematuria in anyone >40 years is bladder cancer until proven otherwise!
- CT urography is the diagnostic imaging of choice in the work up of hematuria.
- Diagnosis of bladder cancer is often delayed due to similarity of symptoms with other benign disorders. However, majority of cases are still caught in stage 0-1 (muscle non-invasive disease) with overall good prognosis.
- Most common malignancy of the urinary system, 3-4 x more common in men but women are usually diagnosed with more advanced disease and have a higher mortality rate.
- Median age at diagnosis is ~70
- Incidence has increased by more than 50% during the past 20-30 years.
- Urothelial (transitional cell) carcinoma is the predominant histologic subtype in the US and Europe (>90% of all bladder cancers) and can arise in renal pelvis, ureter, or urethra
- Other: squamous, adeno, small cell, sarcoma
- Degree of invasion:
- Superficial (non-muscle-invasive)
- Clinical presentation
- Painless hematuria
- Irritative voiding symptoms (frequency, urgency, dysuria) – only in 30% of patients
- Sometimes metastases cause the initial symptoms that lead to diagnosis (as in our patient)
- Most cancers eventually become symptomatic
- Diagnosis: often delayed due to similarity of symptoms to other benign d/o
- Urine cytology >98% specific, 12-64% sensitive based on grade of tumor
- TURBT done for diagnosis and staging
- Hematuria from enlarged prostate
- Passage of renal calculi
Source: Nature Outlook.
- Over 50% of people diagnosed with non-invasive disease develop recurrence
- Assess performance status with Karnofsky or Eastern Cooperative Oncology Group scales for older patients before deciding on chemotherapy
- Chemo regimens are often cisplatin-based which carry the side effects of nephrotoxicity, ototoxicity, and neuropathy
Source: Nature Outlook
Refer to this thorough algorithm on UpToDate.
- Incidence of malignancy in microscopic hematuria is ~2-5%
- Incidence of malignancy in macroscopic hematuria is ~20%
Extra pearls on onset of hematuria during voiding:
- Occurs at the beginning? Urethral source
- Discharge noted between voidings or stain on undergarment? Urethral meatus or anterior urethra
- Terminal hematuria? Bladder neck or prostatic urethra
- Throughout voiding? Anywhere in the GU tract