Observations and lessons from the Clinical Experience with the management of patients with COVID-19 infection

Clinical observations and reflections based on clinical experience with management of patients with COVID-19 infection

English translation
Antonios Liolios, MD
Internist, Intensivist

The following clinical observations and reflections are based on the personal clinical experience of Dr. Ioannis Baraboutis, internal medicine and infectious diseases specialist, combined with his constant communication with other physicians treating patients with COVID-19 infection (first line or not) in Hospitals all over Greece and abroad.

Special thanks to:

-Dr Panagiotis Gargalianos MD, President of the Greek Society of Infectious Diseases. Dr Gargalianos coordinates the regular issuing of updated therapeutic and management national guidelines.

-Dr Evangelos Giamarellos MD, Professor of Medicine and Infectious Diseases in the University of Athens and Director of the Hellenic Institute for the Study of Sepsis. Dr Giamarellos and his colleagues are involved in pioneering research on pathophysiology and management of serious complications of COVID-19 infection and sepsis in general.

I would like to express my gratitude and sincere thankfulness to all the above.

Please see the note at the end of the chapter about the validity of the clinical experience in urgent times of limited data.

Fluids and Electrolytes

Aggressive hydration is discouraged. It is probably better to try and keep the patients on slightly negative fluid balance, especially those with high BMI, cardiac, renal and/or liver disease.

Intravenous medication should be administered with the minimum amount of fluids possible. In patients with a high creative phosphokinase (CPK) (commonly seen in COVID-19 patients) and without evidence of renal tubular dysfunction/acute kidney injury, vigorous hydration should be avoided, especially when CPK is less than  10.000 units/L.  These patients should be closely monitored though for worsening renal function.

If fluids are administered, the concomitant administration of a loop diuretic should be considered.

NUTRITIONAL SUPORT

 Malnourished patients should be given early nutrition and IV supplementation with multivitamin complexes (Evaton in Greece) should be considered for frail/malnourished patients with chronic comorbidities,

according to Greek and international guidelines. A dietician’s input is valuable and various nutritional screening tools should be used. (Examples are MUST (Malnutrition Universal Screening Tool), or NRS2002 (Nutritional Risk Screening 2002 or others)

ANTIPYRETICS

NSAIDs should be avoided, especially in the presence of other contraindications for their use, i.e. advanced age, history of heart failure and/or chronic kidney failure.

Aggressive pyrexia control using paracetamol should be avoided, especially when the fever is well tolerated.

It is possible that a fever in the vicinity of 38 degrees Celsius may actually be beneficial for the patient.

A practice of using Paracetamol tab or IV 500 mg every 8-12 hours for temperature over 38.6 or so could be implemented.

ANTICAOGULATION THERAPY

All patients should receive from admission prophylactic anticoagulation therapy, adjusted for body weight and renal function.

Patients with atrial fibrillation, new or old, better be placed on therapeutic dose of low molecular weight heparin (LMWH) instead of coumadin/warfarin or NOACs. On discharge, coumadin/warfarin or NOACs can be reinstituted to the patients taking them on admission.

When pulmonary embolism (PE) or Deep Vein Thrombosis (DVT) is strongly suspected, therapeutic LMWH should be administered immediately.

If possible, studies using intravenous contrast should be avoided, especially during the time frame of 7 – 12 days after symptom onset or during clinical deterioration. It has been reported (in various pertinent medical fora) that it can worsen the respiratory status and predispose to intubation and ARDS.

  

Computed Tomography of the chest with pulmonary artery protocol (CTPA) could potentially be postponed and done later and after clinical improvement. In the meantime, diagnosis could be pursued through alternative tests (extremity Doppler, [indicative ECG, cardiac echo, V-Q scan if available and deemed appropriate) 

Due to increasing reports of hypercoagulability in COVID-19 infection, therapeutic dose of LMWH for a few days should also be considered in the following patients (even in the absence of atrial fibrillation or confirmed/suspected DVT/PE) :

•High BMI

•Raised D-dimers,  4-5 / fold the upper normal limit

•Clinical deterioration with worsening ARDS

•Clinical deterioration and unexplained hypoxia

Management of patients with COVID-19 and cardiovascular disease

Please refer to the appropriate society guidelines

ACE inhibitors and ARB

We now know that the virus attaches to the receptor of the angiotensin-converting enzyme 2, so concerns have been raised about the patients taking angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Currently, international guidelines suggest that these patients should continue taking their medication unless they develop side effects or worsening renal function.

Based on our clinical experience so far, we haven’t observed significant worsening of renal function attributable to ACEI/ARB, at least in those without a significant preexisting renal failure.

On the other hand, ACEI/ARBs better not be started during hospitalization pending more data. If the patient develops hypertension, pertinent guidelines should be followed and calcium channels inhibitors should be favored if possible.

.  

Specific antiviral therapy

●Kaletra (fixed dose lopinavir/ritonavir) should be used in consultation only with an infectious disease specialist as it may be associated with significant gastrointestinal side effects (epigastric discomfort, nausea, vomiting, especially with concomitant use of azithromycin -, and diarrhea). Additionally, its efficacy and the optimal time of administration have not been yet established.

●The antiviral medication Remdesivir is currently available only via expanded access protocols primarily intended for intubated patients. Studies are currently examining its efficacy in the first 1 – 2 weeks of the infection and the results are awaited.

●Antiviral treatment could be possibly helpful in the following situations:

1.     CNS viral infection (true SARS-CoV-2 encephalitis), only after other etiologies such as sepsis and/or hypoxic brain injury have been excluded. In this case and in consultation with an infectious disease specialist, a 3-5 day therapeutic trial of Kaletra could be considered, as Kaletra is known from the HIV/AIDS literature to adequately cross the blood-brain barrier and be effective in HIV-related brain insult. Other antivirals, like Remdesivir, could be considered. CNS viral involvement should be meticulously confirmed  with the use of brain CT or MRI and CSF examination (quantitative/qualitative PCR and antibodies, depending on local and referral center availability)

2.   Documented or highly suspected direct SARS-CoV-2 viral myocarditis, in consultation with an infectious disease specialist and a cardiologist.

Antimicrobial, antifungal and other therapies

When there is suspicion of concurrent bacterial infection or superinfection, appropriate antimicrobial therapy should be instituted promptly. The combination of the clinical picture (a deteriorating patient) and radiological/laboratory findings can assist in early patient identification.

 

Choice of initial antimicrobials

If the patient is admitted from home, has no recent hospital admissions and no risk factors for colonization/infection by multiresistant gram positive/negative pathogens and he develops fever and CXR infiltrates (especially consolidation), effective antimicrobials against community acquired pneumonia pathogens, based on local guidelines, could be administered. 

Suggested regimes (list not inclusive)  are Ceftriaxone+Azithromycin or Amoxicillin+azithromycin or Amoxicillin/clavulanate+Azithromycin or Teicoplanin+Azithromycin).

Azithromycin could be given orally if tolerated, also intravenously. ECG should be appropriately monitored for QTc prolongation.

In case of azithromycin allergy or intolerance, oral doxycycline or even tigecycline IV could be used (beware of dropping fibrinogen levels with tigecycline use).

Teicoplanin can be used initially or later during the course of the illness if initial regime not deemed effective. There are data supporting its direct antiviral action, there is published clinical experience with its use, it is a well-known antimicrobial with few drug interactions, low toxicity and can even be administered intramuscularly besides intravenously.

The use of the respiratory quinolones (moxifloxacin, levofloxacin) can be considered only as alternatives at this stage, as experience with their use in COVID-19 patients is scant and they can cause QTc prolongation.

Ciprofloxacin can be considered in patients with proven severe respiratory tract  infection  with pseudomonas or other sensitive gram-negative bacteria and in patients with infections in other areas (ie urosepsis). In this case QTc should be closely monitored.

If the patient is clinically deteriorating, there is concern of regime failure or/if the patient develops a new healthcare-associated infection, blood/urine/sputum cultures should be taken and the initial antibiotic regime should be reconsidered and expanded. Local antimicrobial susceptibility should be taken into account. 
Proposed regimens at this stage are teicoplanin + piperacillin/tazobactam or linezolid + imipenem/meropenem/ertapenem or other similar combinations. A team approach including the infectious disease specialist and the microbiologist is of paramount importance.

Vancomycin is not a first choice drug because of slow and limited efficacy in severe respiratory infections in general as well as need for therapeutic drug monitoring, not practical in some settings. Daptomycin is inactivated by the lung surfactant and is thus not recommended.

In patients who develop lung infiltrates and who have been given ciprofloxacin recently, staphylococcal and especially methicillin-resistant staphylococcus aureus (MRSA) pneumonia should be suspected and appropriate treatment should be administered. 

Some patients acutely drop their lymphocyte count to levels below 1000/cubic millimeter and even lower. At this stage of the disease, these patients could behave as ‘acutely immunosuppressed’ and possibly be at risk for infections caused by an expanded spectrum of pathogens, including multi-resistant healthcare associated gram-positive or negative pathogens and other environmental/opportunistic pathogens (for example, Aspergillus spp, Cryptococcus spp complexes, Candida spp, among others).

Patients have presented with otherwise unexplained oral or even esophageal candidiasis around day 7 of symptoms, coinciding with development of the acute lymphopenia. There is published literature showing transient significant drops in the numbers of all sub-types of lymphocytes, especially CD4 and CD8, akin to patients with HIV/AIDS.

In such patients (in-hospital, decreasing total lymphocyte count, worsening infiltrates on CXR/CT of the chest, worsening ARDS), it would make sense, in addition to a broad spectrum antimicrobial regime for healthcare-associated pathogens, to consider using intravenous trimethoprim/sulfamethoxazole and steroids (as in Pneumocystis jiroveci treatment from the AIDS era). This maneuver provides additional antimicrobial coverage and antifungal coverage plus helps as anti-inflammatory regime and -again judging from the AIDS era – could have even direct antiviral properties.

Needless to say that an aggressive diagnostic work should be undertaken at this stage, including bronchoscopy with bronchoalveolar lavage, new blood, urine and sputum cultures and real-time multiplex PCR techniques for identification of bacteria and Candida species, depending on availability.

Any positive culture at this stage of the disease is probably worth treating aggressively, including culture results normally discarded as contaminants (Candida in sputum etc).

Therapy should be continued until clinical improvement and recovery of the lymphocyte count.

Therapy should also be combined with enrollment in diagnostic/therapeutic trials if possible.

COMMENT 1

Fungal infection of the upper or lower respiratory and/or gastrointestinal tract, especially during day 7 to 10 since onset of symptoms, (with or without previous antimicrobial administration) may indicate severe disease and high risk for intubation (remains to be confirmed by clinical trials) 

COMMENT 2: PRACTICAL ASPECTS OF ANTIBIOTIC SELECTION AND DURATION IN WORSENING PATIENTS WITH COVID-19 SUSPECTED OF HAVING SUPERINFECTION

There is shared anecdotal clinical experience among infectious disease specialists that 3 to 5 days of effective antimicrobial therapy may lead to clinical, laboratory and EVEN RADIOLOGICAL improvement in a significant percentage of patients with worsening COVID-19 infection.

So far and based on our clinical experience side effects and complications directly related to the above-described therapeutic strategy (allergies, superinfections from multiresistant bacteria or infection with Clostridioides difficile) have been rare. This indirectly supports the appropriateness of this approach even when there are no sufficient microbiological data confirming an infection/superinfection. The side-effects we observed either happened to patients with mild disease that probably did not need an antimicrobial in the first place or after the 5^th day of treatment (see comment 2).

CORTICOSTEROIDS AND OTHER IMMUNOMODULATORY THERAPIES

Steroids should be used with caution as acute lymphopenia is common in the early stages of COVID-19 infection. Most international organizations advise against steroids especially during the initial stages of the disease.

When steroids are deemed necessary in the initial phase of the disease for other reasons (for example COPD or asthma exacerbation), antimicrobials should be considered earlier, with azithromycin or doxycycline being a reasonable initial choice. Antivirals are currently been tested for administration during this phase, always in consultation with an infectious disease specialist.

If the patient develops ARDS, steroids should be administered according to the already existing protocols, in collaboration with a critical care physician.

It is of note that when methylprednisolone was administered 0.5-1 mg/kg/day (dose not to exceed 2 mg/kg) to some rapidly worsening patients or patients with severe disease in China, positive results were observed without negative effects on the development of immunity.

The already existing experience and literature about the use of steroids in SARS patients (symptomatic improvement, slowing of clinical deterioration, acceleration of infiltrate resolution - but no decrease in length of stay-) could help us until more specific clinical data become available.

COMMENT

Severe/prolonged rigors in day 7 – 10 from the beginning of symptoms (lasting usually 2 – 3 days) could be a harbinger of the cytokine release syndrome (CRS). It is important to try and enroll patients in ongoing clinical studies measuring biological indices and testing immunomodulatory therapies.

Such studies are currently being conducted by Professor E. Giamarellos in Greece. (Hellenic Institute for the Study of Sepsis, studies ESCAPE and SAVΕ)

If study enrollment or access to immunomodulatory therapy are not possible, steroid administration should be considered in case of respiratory status deterioration, suggested PaO2/FiO2 in the area of 200-250. A suggested regime is dexamethasone 8 mg every 6 hours or methylprednisolone 0.5 – 1 mg/kg for 2 – 3 days and then tapering. Steroids should be given along with appropriate antimicrobials, antiviral or other therapy and in consultation with an infectious disease specialist.

OTHER PHARMACEUTICAL / SUPPORTIVE THERAPY AND MANAGEMENT

Proning or lateral positioning could benefit patients with increasing respiratory effort and hypoxia and can help avoid intubation. Prerequisites are good patient cooperation and constant direct visual observation by the medical and nursing staff.

When using the lateral position, a recent CXR can help choose the side as the patient should be turned to the side with the more extensive infiltrates. Secretion pooling and atelectasis should be carefully monitored and avoided.

If the patient develops delirium, a delirium work up used in non-COVID-19 patients should be initiated (for example head CT, thyroid function, B12/folate levels etc) in addition to COVID-19 management.

It is of paramount importance to realise the psychological impact the disease can have on patients. Isolation and separation from family and friends, inability to recognise the faces of the medical providers due to protective equipment,  hypoxia, fear, anxiety, all could contribute to the development of a mental health disorder, possibly a type of post traumatic stress disorder as it was seen in the SARS patients.

In one case, a patient that finally escaped intubation and ARDS but had to be kept in the High Dependency Unit area for several days, became close witness of 4 intubations. Later on his relatives mentioned that the patient had told them he thought all the intubated patients had died. He was immensely relieved when he was explained that all the intubated patients were actually alive. 

Input of an experienced psychiatrist is invaluable. Caution should be exercised with psychiatric drug interactions (for example quetiapine and QTc prolongation)

TRANSFUSIONS

Blood and blood products transfusions should be given according to available Greek and international guidelines. Because of the pandemic situation and lockdowns a blood shortage for regularly transfused patients should be expected (as it happened in Italy). In this case hematologists should provide an alternative solution.

SURGERY AND INVASIVE PROCEDURES 

In case surgery or any other invasive procedure is necessary, local and international guidelines should be followed for appropriate prioritization. Collaboration of the surgeon or the invasive specialist with the Infectious Diseases specialist is essential.

MOBILIZATION – PHYSIOTHERAPY – REHABILITATION

Patients’ mobility should be preserved. Recovering patients from moderate or severe disease should be mobilized early and begin aggressive physiotherapy in the context of a specific rehabilitation plan, always in accordance with local and international guidelines.

SUPPORT OF THE PATIENT WITH ARDS AND THE TERMINALLY ILL PATIENT

Intubated patients with ARDS should be cared by a multidisciplinary team of pulmonologists, anesthesiologists and intensivists. Patient enrollment into studies should be done according to local and international law and ethics.

According to the principles of palliative medicine, management of pain, dyspnea, agitation, and anxiety in terminally ill patients is of paramount importance. At this stage, psychological and religious support are also very important (see below).

Religious support of patients and their families

Religious and spiritual support is very important for patients. In Greece the majority of patients are Christian Orthodox so the harmonious collaboration of State and Church is of great significance. The State should provide all the necessary technical support so patients and families have access to religious and spiritual services.

The same measures should apply to members of all other denominations and religions.

Social services

Social services should be available to all patients and families.

Personal data protection

Personal data of οf patients, families and involved health care providers should be protected and not shared with the public.

Informing the patients and complaint registry

Patients and families should be regularly informed and updated about their condition, in accordance to Greek and international guidelines. The process should be conducted with respect to their wishes and in a humane manner, with understanding and patience.

Complaints and suggestions for improvement should be registered and taken into account for future planning

Informing the public, media and social networks

Informing the public via the media and social networks should be done in an ethical and deontological way. Regarding private social networks, personal responsibility and accountability should prevail. Citizens should be discouraged from sharing personal data of hospitalised patients or relatives.

The role of pharmaceutical companies and hospital material providers

The state should collaborate effectively with the pharmaceutical and hospital material providers in order to prevent shortages of medications and other vital materials such as ventilators and other equipment.

During the pandemic, all medications provided by the pharmaceutical companies, old or new, may be useful.

Alternative therapies

Traditional and alternative medicine is widespread in China, which was the first country to be hit by the pandemic. This form of medicine was widely applied to patients with COVID-19 aiming to “enhance” the immune system, ameliorate the symptoms and protect from contacting and spreading the disease.

There are many studies and clinical experience in developed countries examining the effect of plant- and herb- based medications on patients with chronic conditions such as end-stage cancer and AIDS. Some patients report improvement of their symptoms. On the other hand, some of these regimes interact with the other conventional medications the patient is taking.

Recently, there is an increased interest in some of the substances contained in these regimen, called flavonoids.  Flavonoids’ effects on various diseases and their use as anti-aging agents is currently been studied. There are some limited laboratory data suggesting that flavonoids can inhibit various viral enzymes. including coronaviruses.

Based on the above, at this point the use of these substances by patients with COVID-19 or by the general public cannot be recommended.

  

Taking into account the absence of effective therapy and vaccine for COVID-19, if a patient wishes to use a traditional/alternative regimen, he should sign a release form and the regime should be checked for possible interactions with the rest of his medications. 

Further imaging and laboratory follow up

Repeat the CXR every 2-3 days or earlier if there is deterioration. The clinical picture does NOT often correlate with the radiological findings. There are cases where after the administration of the appropriate antibiotic therapy, improvement of the CXR findings happened quite fast in comparison with classic community- or healthcare- acquired pneumonias.

It is worthwhile to obtain a pre-discharge CXR and repeat one 4-6 weeks later, according to Greek and international guidelines issued by the Pulmonary and Infectious diseases societies.

The most important laboratory markers predictive of clinical deterioration are lymphopenia, neutrophilia, raised CRP and raised ferritin. Procalcitonin could also help when there is suspicion of a bacterial infection.

COMMENT

The inflammatory markers CRP and ferritin appear to rise in parallel but NOT always.

For example, the trend of decreasing CRP appears to correlate with clinical improvement, especially when a bacterial superinfection is likely to be present, but ferritin may follow a different course.

Ferritin appears to decrease more slowly in patients with clinical improvement and follows different kinetics. Cases of asymptomatic rise and fall of both inflammatory markers, especially ferritin, later in the course of the disease (close to 2 weeks from symptom onset) have been observed.   

It is possible that CRP mainly reflects the presence of superinfection and less the presence of “viral inflammation”, while ferritin may be associated with both and, even more, with viral replication and viral load, a hypothesis that remains to be confirmed or discarded. 

Post-discharge directions

There are data that COVID-19 patients appear shed the virus in their stool for a prolonged period of time, so the patient should take precautions at home similar to those taken for hepatitis A for as long as possible. There should be close communication and follow up with the family physician.

Suggested general post-discharge recommendations – always need to be individualized for the particular patients - are the following:

-1 to 2 weeks after discharge, repeat CBC, full biochemical profile, CRP, ferritin, ESR and any other test done during the hospital stay as judged by the treating physician.

- If the discharge CXR was abnormal repeat CXR after 4-6 weeks. If there is a suspicion of malignancy, follow up should be according to existing guidelines.

-In case there were findings in the Chest CT but not in the CXR, further management should be done in consultation with an infectious disease specialist and a pulmonologist.

-Repeat EKG 5-7 days after discharge. If there are abnormal EKG findings or if the patient develops symptoms suggestive of cardiac disease, cardiology input should be obtained.

-Hospitals exclusively treating patients with COVID-19 infection could organise an outpatient medical clinic for their discharged patients.

The central role of the internist/infectious disease specialist and collaboration with other medical specialties.

According to currently available data, COVID-19 causes severe disease primarily in older patients with one or more comorbidities.

Internal medicine and infectious diseases specialists are the most appropriate physicians to coordinate the general management and final decision making in patients with COVID-19. 

Because of patient complexity and multiple organ involvement, these specialists should be supported by specialists from all other medical disciplines and work together as a Multi-Disciplinary Team (MDT). This collaboration does not always require physical presence and can be performed remotely as well.

Besides physicians, essential MDT members are nurses, physical therapists, dieticians and social workers.

Infection control nurses play a pivotal role in these teams and should be supported by the Infectious Diseases Hospital committees and other relevant State bodies.

COMMENT ON THE CONCEPT OF CLINICAL EXPERIENCE AND CLINICAL INSTINCTS

Most of the points, bullets and suggestions outlined in this section of the e-book were – and some of them still are - written based solely on personal and collective ‘clinical experience’ of physicians who treated patients with COVID-19 infection. At least initially, a significant portion of the section was not supported by classical scientific proof, based on appropriate clinical local or international studies, simply because those were non-existent or inconclusive or not widely applicable or with results pending. Needless to say that frequent monitoring and filtering of various literature trails is essential to have those points either verified or discarded.

This infection has successfully been named as ‘asymmetric threat’. Using key elements from the US Department of Defense definition of unconventional warfare, the asymmetric threat can be defined as "a broad and unpredictable spectrum of military, paramilitary, and information operations, conducted by nations, organizations, or individuals or by indigenous or surrogate forces under their control, specifically targeting weaknesses and vulnerabilities within an enemy government or armed force''. This practically means that when facing an unknown and possibly superior enemy or a poorly-defined and ominous situation, one way to respond that has been proven successful in the past is to ‘go unorthodox and unconventional’ and take ‘calculated risks’ to prevent huge losses.

Accordingly, when it comes to facing a pandemic from an ‘unknown’ virus that has caused absolute carnage in several countries, the clinician may be forced to promptly respond based on mainly his/her ‘gut feeling’ or ‘intuition’ and less on solid scientific data, taking calculated risks with his/her therapeutic maneuvers. This is NOT equivalent to ‘experimentation’ or ‘basic instincts’, it is a spectrum of much more complex mental processes, currently being vigorously researched in the management, learning and creativity literature (see last reference).

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